WO2022068877A1 - Pharmaceutical compositions of amorphous solid dispersions and methods of preperation thereof - Google Patents

Pharmaceutical compositions of amorphous solid dispersions and methods of preperation thereof Download PDF

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Publication number
WO2022068877A1
WO2022068877A1 PCT/CN2021/121696 CN2021121696W WO2022068877A1 WO 2022068877 A1 WO2022068877 A1 WO 2022068877A1 CN 2021121696 W CN2021121696 W CN 2021121696W WO 2022068877 A1 WO2022068877 A1 WO 2022068877A1
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Prior art keywords
acid
amorphous solid
solid dispersion
api
palbociclib
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PCT/CN2021/121696
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English (en)
French (fr)
Inventor
Zeren Wang
Shun Chen
Longwei Sun
Yanxin Zhao
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Shenzhen Pharmacin Co Ltd
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Shenzhen Pharmacin Co Ltd
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Priority to US18/028,651 priority Critical patent/US20240335390A9/en
Priority to CA3194010A priority patent/CA3194010A1/en
Priority to MX2023003689A priority patent/MX2023003689A/es
Priority to CN202180076133.5A priority patent/CN116847831A/zh
Priority to AU2021351818A priority patent/AU2021351818A1/en
Priority to KR1020237014222A priority patent/KR20230097027A/ko
Priority to EP21874532.1A priority patent/EP4221691A4/en
Priority to JP2023519416A priority patent/JP2023543814A/ja
Publication of WO2022068877A1 publication Critical patent/WO2022068877A1/en
Anticipated expiration legal-status Critical
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Definitions

  • Palbociclib and neratinib are approved for use and sale in the United States. According to the palbociclib product label, one of seven patients has poor absorption upon administration of the palbociclib product. The poor solubility of the drug contributes to the poor absorption in patients. Additionally, according to the product label of neratinib maleate, the compound is insoluble at pH 5.0, and only sparingly soluble at pH 1.2.
  • compositions of amorphous solid dispersions and pharmaceutical compositions comprising an active pharmaceutical ingredient (API) , or a salt or solvate thereof, and methods of making and using the same.
  • the amorphous solid dispersion comprises one or more acids.
  • the amorphous solid dispersion comprises a first acid and a second acid.
  • an amorphous solid dispersion wherein the amorphous solid dispersion comprises: a first acid, wherein the first acid is an organic acid that has a pKa of at most 2; a second acid, wherein the second acid has a pKa greater than 2; a hydrophilic high-molecular weight material; and palbociclib, a salt of palbociclib, or any combination thereof, wherein the molar ratio of the first acid to palbociclib is from about 0.5: 1 to about 5: 1, and wherein the weight ratio of the second acid to palbociclib is from about 0.1: 1 to about 10: 1.
  • the salt of palbociclib comprises the first acid.
  • the salt of palbociclib comprises palbociclib and the first acid.
  • an amorphous solid dispersion wherein the amorphous solid dispersion comprises: a first acid, wherein the first acid is an acid that has a pKa of at most 2; a second acid, wherein the second acid has a pKa greater than 2; a hydrophilic high-molecular weight material; and palbociclib, a salt of palbociclib, or any combination thereof, wherein a molar ratio of the first acid to palbociclib is from about 0.5: 1 to about 3: 1, and wherein a weight ratio of the second acid to palbociclib is from about 0.2: 1 to about 1.5: 1.
  • the salt of palbociclib comprises the first acid.
  • an amorphous solid dispersion wherein the amorphous solid dispersion comprises: a) a first acid, wherein the first acid is an organic acid that has a pKa of at most 2; b) a second acid, wherein the second acid has a pKa greater than 2; c) a hydrophilic high-molecular weight material; and d) an active pharmaceutical ingredient (API) , a pharmaceutically acceptable salt of the API, or any combination thereof, wherein the molar ratio of the first acid to API is from about 0.5: 1 to about 5: 1, and wherein the weight ratio of the second acid to API is from about 0.1: 1 to about 10: 1.
  • the salt of the API comprises the first acid.
  • an amorphous solid dispersion wherein the amorphous solid dispersion comprises: a) an active pharmaceutical ingredient (API) , wherein the API is at least partially protonated, and wherein the API has a logP of at least 2; b) one or more acids; and c) a hydrophilic high-molecular weight material, wherein a molar ratio of the one or more acids to the API is from about 0.1: 1 to about 20: 1.
  • API active pharmaceutical ingredient
  • amorphous solid dispersion wherein the amorphous solid dispersion comprises:
  • API active pharmaceutical ingredient
  • - is a single bond or a double bond
  • R 1 is C 1 -C 6 alkyl
  • R 3 is C 1 -C 8 alkoxy, C 3 -C 7 cycloalkyl, or C 3 -C 7 -heterocyclyl;
  • R 2 and R 4 are each independently hydrogen, halogen, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 hydroxyalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, nitrile, nitro, -OR 10 , -SR 10 , -NR 10 R 11 , -N (O) R 10 R 11 , -P (O) (OR 10 ) (OR 11 ) , - (CR 10 R 11 ) m NR 12 R 13 , -COR 10 , - (CR 10 R 11 ) m C (O) R 12 , -CO 2 R 10 , -CONR 10 R 11 , -C (O) NR 10 SO 2 R 11
  • each of R 5 , R 6 , and R 7 is independently hydrogen, halogen, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 1 -C 8 alkoxy, -C 1 -C 8 alkoxyalkyl, -CN, -NO 2 , -OR 10 , -NR 10 R 11 , -CO 2 R 10 , -COR 10 , -S (O) n R 10 , -CONR 10 R 11 , -NR 10 COR 11 , -NR 10 SO 2 R 11 , -SO 2 NR 10 R 11 , or -P (O) (OR 10 ) (OR 11 ) ;
  • each of R 10 , R 11 , R 12 and R 13 is independently hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • - m is 0, 1, 2, 3, 4, 5, or 6;
  • - n is 0, 1 or 2; b) a first acid, wherein the first acid is an organic acid that has a pKa of at most 2; c) a second acid, wherein the second acid has a pKa greater than 2; and d) a hydrophilic high-molecular weight material, wherein a molar ratio of the first acid to Formula (I) is from about 0.5: 1 to about 5: 1, and wherein a weight ratio of the second acid to Formula (I) is from about 0.1: 1 to about 10: 1.
  • the salt of Formula (I) comprises the first acid.
  • amorphous solid dispersion wherein the amorphous solid dispersion comprises: a) a pharmaceutically acceptable salt of neratinib; and b) a hydrophilic high-molecular weight material.
  • an amorphous solid dispersion wherein the amorphous solid dispersion comprises: a) neratinib, or a pharmaceutically acceptable salt thereof; b) two or more pharmaceutically acceptable acids; and c) a hydrophilic high-molecular weight material, wherein the pharmaceutically acceptable salt of neratinib comprises neratinib and at least one of the two or more pharmaceutically acceptable acids, and wherein a molar ratio of the two or more acids to the API is from about 0.1: 1 to about 20: 1.
  • amorphous solid dispersion wherein the amorphous solid dispersion comprises:
  • API active pharmaceutical ingredient
  • R 1 is halogen
  • R 2 is a pyridinyl, thiophene, pyrimidine, thiazole, or phenyl, each of which is optionally substituted with up to three substituents;
  • - R 3 is -O-or -S-;
  • R 4 is C 1-3 alkyl or C 1-3 heteroalkyl
  • R 5 is ethyl or methyl
  • - n is 0 or 1;
  • composition wherein the pharmaceutical composition comprises: a) an amorphous solid dispersion as described herein, and b) one or more pharmaceutically acceptable carriers or excipients.
  • a pharmaceutical composition comprising: a) an amorphous solid dispersion, the amorphous solid dispersion comprising: i. an active pharmaceutical ingredient (API) , a pharmaceutically acceptable salt thereof, or any combination thereof; ii. one or more interior acids; iii. a hydrophilic high-molecular weight material; and iv. optionally, an adsorbent; b) one or more exterior acids; c) one or more pharmaceutically acceptable carriers or excipients, wherein the mass ratio of the one or more exterior acids to API is from about 0.1 to about 1: 1.
  • API active pharmaceutical ingredient
  • a method of manufacturing a pharmaceutical composition comprising an amorphous solid dispersion, the method comprising: (a) combining (i) a first acid, wherein the first acid is an organic acid that has a pKa of at most 2; (ii) a second acid, wherein the second acid has a pKa greater than 2; and (iii) a hydrophilic high-molecular weight material, (iv) palbociclib, a salt of palbociclib, or any combination thereof, wherein the salt of palbociclib comprises palbociclib and the first acid; wherein the molar ratio of the first acid to palbociclib is from about 0.5: 1 to about 5: 1, and wherein the weight ratio of the second acid to palbociclib is from about 0.1: 1 to about 10: 1, (v) a solvent; thereby producing a mixture; (b) removing at least a portion of the solvent from the mixture, thereby producing an amorphous solid dispersion; and (c
  • a method of manufacturing an amorphous solid dispersion comprising: (a) combining (i) palbociclib, wherein the palbociclib is at least partially protonated; (ii) a first acid, wherein the first acid is an organic acid that has a pKa of at most 2; (iii) a second acid, wherein the second acid has a pKa greater than 2; and (iv) a hydrophilic high-molecular weight material, wherein the molar ratio of the first acid to palbociclib is from about 0.5: 1 to about 5: 1, and wherein the weight ratio of the second acid to palbociclib is from about 0.1: 1 to about 10: 1, (v) a solvent; thereby producing a mixture; and (b) removing at least a portion of the solvent from the mixture, thereby producing an amorphous solid dispersion.
  • Disclosed herein is a method of treating a disease or condition, comprising administering to a subject in need thereof a pharmaceutical composition or an amorphous solid dispersion described herein.
  • the disease or condition is cancer.
  • the disease or condition is breast cancer.
  • a method of inhibiting CDK4/6 in a subject comprising administering to a subject in need thereof a pharmaceutical composition or an amorphous solid dispersion described herein.
  • the amorphous solid dispersion or pharmaceutical composition described herein for the treatment of a disease or condition in a subject.
  • the disease or condition is cancer.
  • the disease or condition is breast cancer.
  • the pharmaceutical composition is administered without regards to food.
  • Figure 1 is a plot of the dissolution rate for amorphous solid dispersions.
  • Figure 2 is a workflow for manufacturing a pharmaceutical composition described herein.
  • Figure 3 is an illustration of a pharmaceutical composition having an inner and an outer matrix.
  • Figure 4 is an illustration of a pharmaceutical composition having an inner and an outer matrix.
  • Figure 5 shows the XRPD of palbociclib ASD Formulations 1, 2, and 3.
  • Figure 6 shows the XRPD of palbociclib ASD Formulations 4, 5, and 6.
  • Figure 7 shows the XRPD of palbociclib ASD Formulations 7, 8, 9, and 10.
  • Figure 8 shows the XRPD of palbociclib ASD Formulations 11, 12, and 13.
  • Figure 9 shows the XRPD of ASD Formulation 14.
  • Figure 10 shows the XRPD of ASD Formulation 21.
  • Figure 11 shows the comparison of XRPD profiles of palbociclib ASD capsule
  • Figure 12 shows the comparison of XRPD Profiles of palbociclib ASD capsule
  • Figure 13 shows the kinetic solubility of palbociclib ASD powders.
  • Figure 14 shows the dissolution profiles of different palbociclib formulations.
  • Figure 15 shows the mean dog plasma palbociclib profiles of after different dosing pretreatments.
  • Figure 16 shows the mean dog plasma palbociclib profiles of Formulation 18 after different dosing pretreatments.
  • Figure 17 shows the XRPD of neratinib maleate ASD Formulations 22, 23, and 24.
  • Figure 18 shows the XRPD of neratinib maleate ASD Formulations 25.
  • Figure 19 shows the XRPD of neratinib maleate ASD Formulations 26.
  • Figure 20 shows the kinetic solubility of neratinib maleate ASD powders.
  • Figure 21 shows the dissolution profiles of different neratinib maleate formulations.
  • the present disclosure relates to pharmaceutical compositions and methods of administering thereof, the pharmaceutical compositions comprising an amorphous solid dispersion comprising an API.
  • the disclosed pharmaceutical composition has increased solubility compared to a corresponding pharmaceutical composition which does not contain amorphous solid dispersion.
  • the disclosed pharmaceutical composition has increased bioavailability compared to a corresponding pharmaceutical composition which does not contain an amorphous solid dispersion.
  • the disclosed pharmaceutical composition has an increased solubility and bioavailability compared to a corresponding pharmaceutical composition without an amorphous solid dispersion.
  • the disclosed pharmaceutical composition has increased absorption compared to a corresponding pharmaceutical composition without an amorphous solid dispersion.
  • the disclosed pharmaceutical composition is less susceptible to food effect compared to a corresponding pharmaceutical composition without an amorphous solid dispersion.
  • formulating an active pharmaceutical ingredient in an amorphous solid dispersion increases stability of the active pharmaceutical ingredient in the pharmaceutical formulation.
  • An exemplary amorphous solid dispersion comprises palbociclib as the API.
  • the solubility of the palbociclib free base in water is poor, which leads to poor absorption and low bioavailability. Additionally, palbociclib free base has a strong adhesive property upon impact, which adhesive property is related to the specific surface area of the particles. If palbociclib free base is reacted with an acid to generate salts so as to increase the solubility, the salts have a poor solid nature and thereby are disadvantageous for being developed as a solid formulation.
  • an amorphous solid dispersions of palbociclib comprises a combination of a weak acid (e.g., an acid having a pKa of greater than 2) , and a strong acid (e.g., an acid having pKa of at most 2) .
  • a strong acid e.g., an acid having a pKa below 2
  • a weak organic acid e.g., an organic acid having a pKa above 2 enables absorption of the palbociclib active ingredient in the gastro-intestinal tract, thereby increasing bioavailability.
  • a palbociclib composition described herein retains at least 98%, e.g., at least 99%, or at least 99.8%of the palbociclib after being stored for at least 3 months at 40°C and 75%relative humidity.
  • a palbociclib composition described herein contains less than about 2%, e.g., less than 1%, or less than 0.2%of a palbociclib degradation product (based on the weight of the initial palbociclib) after being stored for at least 3 months at 40°C and 75%relative humidity.
  • Amorphous solid dispersions of the present disclosure also have a processability advantage.
  • a combination of a weak acid (e.g., an acid having a pKa of greater than 2) , and a strong acid (e.g., an acid having pKa of at most 2) enables formation of amorphous solid dispersions of active pharmaceutical ingredients by spray drying at room temperature and atmospheric pressure, thereby avoiding harsh reaction conditions such as elevated temperature.
  • the palbociclib active ingredient has increased solubility and bioavailability relative to commercially available compositions. Increasing the solubility and bioavailability of drugs can lead to lower drug loadings in pharmaceutical formulations. Such lower loadings benefit the patient by reducing the costs and side effects of the medication.
  • the present disclosure relates to an amorphous solid dispersion comprising a protonated API.
  • the solubility of a drug can be accomplished by the ionization of the drug through protonation of one or more basic sites on the drug, e.g., forming an acidic salt of the drug and administering the salt.
  • protonated drugs can lose of stability and may decompose more quickly under storage conditions.
  • Amorphous solid state dispersions of protonated APIs can enhance stability. Therefore, there is a need for pharmaceutical formulations comprising the described amorphous solid dispersions comprising a protonated API.
  • the need for the formulations described herein is particularly acute in patients with conditions that require treatments that result in the elevation stomach pH.
  • patients suffering from Gastroesophageal Reflux Disease may alleviate symptoms by administering pharmaceutical formulations comprising proton pump inhibitors (PPI) or antacids and raise the pH of the stomach.
  • PPI proton pump inhibitors
  • antacids may be administered by administering pharmaceutical formulations comprising proton pump inhibitors (PPI) or antacids and raise the pH of the stomach.
  • PPI proton pump inhibitors
  • antacids antacids
  • raise the pH of the stomach if a subsequent drug relies on protonation in the stomach to increase dissolution and bioavailability of the drug, an elevated pH in the stomach, will reduce its efficacy.
  • the pharmaceutical compositions and methods described herein increase the dissolution and bioavailability of particular APIs in subjects with stomachs having elevated pH levels due to intake of pH-increasing drugs.
  • amorphous solid dispersions of the present disclosure may be administered without regards to food.
  • amorphous solid dispersions and/or pharmaceutical compositions comprising the amorphous solid dispersions may be administered in the absence of food (e.g., under fasting conditions) .
  • amorphous solid dispersions and/or pharmaceutical compositions comprising the amorphous solid dispersions may be administered in the presence food (e.g., under fed conditions) .
  • the present disclosure relates to an amorphous solid dispersion comprising a protonated API.
  • the unprotonated API is poorly soluble in water or other polar protic solvents.
  • the API is first dissolved to form a solution.
  • a strong acid pKa of less than 2 can be useful to ionize the poorly soluble API such that the protonated API can be dissolved into a solution.
  • a strong organic acid is used to decrease corrosion of the manufacturing equipment.
  • the strong organic acid is an aliphatic sulfonic acid or aromatic sulfonic acid.
  • the strong acid is methanesulfonic acid.
  • the strong acid is ethanesulfonic acid.
  • the strong acids is p-toluene sulfonic acid.
  • the present disclosure relates to an amorphous solid dispersion comprising a protonated API, a first acid with a pKa of less than 2, and a second acid with a pKa more than 2.
  • the first acid is useful in ionizing the API such that the protonated API can dissolve into a solution. Therefore, the molar ratio of the API to the first acid can be an useful parameter.
  • the second acid is useful for maintaining the solubility of the API as the progresses through the gastrointestinal tract. Therefore, the mass ratio of the second acid can be a useful parameter.
  • the first and/or second acids are physically stable and unlikely to form crystals.
  • an API disclosed herein is palbociclib.
  • Palbociclib has two pKa values, 3.9 and 7.4 respectively. When the pH value is below 4, the solubility is high. When the pH value is higher than 4, the solubility of the drug drops significantly to less than about 0.02 mg/ml.
  • the pharmaceutical compositions disclosed herein comprise an amorphous solid dispersion comprising protonated palbociclib. The amorphous solid dispersion substantially increases the bioavailability of palbociclib upon administration, particularly in stomachs with elevated pH levels.
  • an API disclosed herein is neratinib maleate.
  • Neratinib maleate has two pKa values, 4.7 and 7.7 respectively. When the pH value is 1.2, neratinib maleate has a solubility of 32.90 mg/mL. When the pH value is approximately 5.0, the solubility of the drug drops significantly to about 0.08 mg/ml or less.
  • the pharmaceutical compositions disclosed herein comprise an amorphous solid dispersion comprising neratinib maleate.
  • subject refers to a mammal (e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee or baboon) .
  • mammal e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee or baboon.
  • AUC refers to the area under the plasma drug concentration-versus-time curve extrapolated from zero time to infinity.
  • C max refers to the highest drug concentration observed in plasma following an extravascular dose of drug.
  • T max refers to the time after administration of a drug when the maximum plasma concentration is reached.
  • “Therapeutically equivalent” when used in connection with a pharmaceutical composition described herein refers to an amount or quantity of a pharmaceutically acceptable salt of a pharmaceutically active agent that is equivalent to the therapeutically effective amount of the free base of the pharmaceutically active agent.
  • terapéutica means an agent utilized to treat, combat, ameliorate, prevent, or improve an unwanted condition or disease of a patient.
  • administering when used in conjunction with a therapeutic, means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted.
  • administering when used in conjunction with Compound A formulation, can include, but is not limited to, providing Compound A formulation into or onto the target tissue; providing Compound A formulation systemically to a patient by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells.
  • administering a formulation may be accomplished by oral administration or by other methods alone or in combination with other known techniques.
  • a “therapeutically effective amount” or “effective amount” as used herein, refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition, or disorder in an individual that may be predisposed to the disease, condition, or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition, or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.
  • ameliorating the disease for example, ameliorating a disease, condition, or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.e., reversing the pathology and/or symptomatology) .
  • Amino refers to the —NH 2 radical.
  • Niro refers to the -NO 2 radical.
  • Metal refers to the -O-Me radical.
  • Oxa refers to the -O-radical.
  • Haldroxy or “hydroxyl” refers to the -OH radical.
  • Haldroxyamino refers to the -NH-OH radical.
  • Acyl refers to a substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted heterocycloalkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl, amide, or ester, wherein the carbonyl atom of the carbonyl group is the point of attachment.
  • an alkylcarbonyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, amide group, or ester group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • acyl-sulfonamide refers to a monovalent radical where the carbon atom of a carbonyl is bound to a sulfonamide group.
  • exemplary acyl-sulfonamides include -C (O) NR a S (O) 2 R a , -C (O) NR a S (O) 2 N (R a ) 2 , -NR a S (O) 2 C (O) R a , -NR a S (O) 2 C (O) N (R a ) 2 , -C (O) NR a S (O) 2 C (O) N (R a ) 2 , -NR a S (O) 2 NR a C (O) N (R a ) 2 , -C (O) NR a S (O) 2 NR a C (O) N (R a ) 2 , -C (O) NR a S (O) 2 NR a C
  • Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical.
  • An alkyl group can have from one to about twenty carbon atoms, from one to about ten carbon atoms, or from one to six carbon atoms.
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, and longer alkyl groups, such as heptyl, octyl,
  • C 1 -C 6 alkyl means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1 -C 10 alkyl, a C 1 -C 9 alkyl, a C 1 -C 8 alkyl, a C 1 -C 7 alkyl, a C 1 -C 6 alkyl, a C 1 -C 5 alkyl, a C 1 -C 4 alkyl, a C 1 -C 3 alkyl, a C 1 -C 2 alkyl, or a C 1 alkyl.
  • an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , -NO 2 , or -C ⁇ CH.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds.
  • an alkenyl group has from two to about ten carbon atoms, or two to about six carbon atoms. The group may be in either the cis or trans configuration about the double bond (s) , and should be understood to include both isomers.
  • a numerical range such as “C 2 -C 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • the alkenyl is a C 2 -C 10 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl.
  • an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds.
  • an alkynyl group has from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like.
  • C 2 -C 6 alkynyl means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • the alkynyl is a C 2 -C 10 alkynyl, a C 2 -C 9 alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 7 alkynyl, a C 2 -C 6 alkynyl, a C 2 -C 5 alkynyl, a C 2 -C 4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl.
  • an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkylene is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. In some embodiments, the alkylene is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -. In some embodiments, the alkylene is -CH 2 -. In some embodiments, the alkylene is -CH 2 CH 2 -. In some embodiments, the alkylene is -CH 2 CH 2 CH 2 -.
  • Alkylamino refers to a radical of the formula -N (R a ) 2 where R a is an alkyl radical as defined, or two R a , taken together with the nitrogen atom, can form a substituted or unsubstituted C 2 -C 7 heterocyloalkyl ring. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkylamino is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, an alkylamino is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the alkylamino is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Hydroxyalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising at least one aromatic ring.
  • an aryl comprises hydrogens and 6 to 30 carbon atoms.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6-to 10-membered aryl.
  • the aryl is a 6-membered aryl.
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • the aryl is phenyl.
  • an aryl may be optionally substituted, for example, with halogen, amino, alkylamino, aminoalkyl, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -S (O) 2 NH-C 1 -C 6 alkyl, and the like.
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , -NO 2 , -S (O) 2 NH 2 , -S (O) 2 NHCH 3, -S (O) 2 NHCH 2 CH 3 , -S (O) 2 NHCH ( CH 3 ) 2 , -S (O) 2 N (CH 3 ) 2 , or -S (O) 2 NHC (CH 3 ) 3 .
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • the aryl is substituted with alkyl, alkenyl, alkynyl, haloalkyl, or heteroalkyl, wherein each alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl is independently unsubstituted, or substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2.
  • Cycloalkyl refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , bridged, or spiro ring systems.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 cycloalkyl) , from three to ten carbon atoms (C 3 -C 10 cycloalkyl) , from three to eight carbon atoms (C 3 -C 8 cycloalkyl) , from three to six carbon atoms (C 3 -C 6 cycloalkyl) , from three to five carbon atoms (C 3 -C 5 cycloalkyl) , or three to four carbon atoms (C 3 -C 4 cycloalkyl) .
  • the cycloalkyl is a 3-to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5-to 6-membered cycloalkyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
  • Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halogens. In some embodiments, the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens. Haloalkyl can include, for example, iodoalkyl, bromoalkyl, chloroalkyl, and fluoroalkyl.
  • fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , or -CH (CH 3 ) OCH 3 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Heterocyclyl, “ “heterocycle, ” or “heterocyclic” refers to a stable 3-to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused, bridged, or spirocyclic ring systems.
  • the heteroatoms in the heterocyclyl radical are optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heterocyclyl radical is partially or fully saturated.
  • heterocyclyl is attached to the rest of the molecule through any atom of the ring (s) .
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyr
  • heterocyclyl is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC (O) -R a , -R b -OC (O) -OR a , -R b -OC (O)
  • Heterocycloalkyl refers to a stable 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -C 15 heterocycloalkyl) , from two to ten carbon atoms (C 2 -C 10 heterocycloalkyl) , from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl) , from two to six carbon atoms (C 2 -C 6 heterocycloalkyl) , from two to five carbon atoms (C 2 -C 5 heterocycloalkyl) , or two to four carbon atoms (C 2 -C 4 heterocycloalkyl) .
  • the heterocycloalkyl is a 3-to 6-membered heterocycloalkyl. In some embodiments, the cycloalkyl is a 5-to 6-membered heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides, and the oligosaccharides. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) .
  • a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a ring system radical comprising carbon atom (s) and one or more ring heteroatoms that are selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • a heteroaryl is a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5-to 10-membered heteroaryl.
  • the heteroaryl is a 5-to 6-membered heteroaryl.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, fur
  • a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • C 1 -C x (or C 1-x ) includes C 1 -C 2 , C 1 -C 3 . . . C 1 -C x .
  • a group designated as “C 1 -C 4 ” indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • treat, ” “prevent, ” “ameliorate, ” and “inhibit, ” as well as words stemming therefrom, as used herein, do not necessarily imply 100%or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect.
  • the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal.
  • a disorder, including symptoms or conditions thereof may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.
  • treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease.
  • treatment, ” “prevention, ” “amelioration, ” or “inhibition” encompass delaying the onset of the disorder, or a symptom or condition thereof.
  • “treating” includes the concepts of “alleviating” , which refers to lessening the frequency of occurrence or recurrence, or the severity, of any symptoms or other ill effects related to a disorder and/or the associated side effects.
  • treating also encompasses the concept of “managing” which refers to reducing the severity of a particular disease or disorder in a patient or delaying its recurrence, e.g., lengthening the period of remission in a patient who had suffered from the disease.
  • treating further encompasses the concept of “prevent, ” “preventing, ” and “prevention, ” that is, reducing the probability of developing a disease or condition in a subject, who does not have, but is at risk of or susceptible to developing a disease or condition.
  • an optionally substituted group may be un-substituted (e.g., -CH 2 CH 3 ) , fully substituted (e.g., -CF 2 CF 3 ) , mono-substituted (e.g., -CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc. ) .
  • substituted means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom (s) to satisfy the valences described or shown.
  • the point of attachment may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure.
  • a person of ordinary skill in the art would understand that, while only a single bond is shown, a double bond is intended for those substituents.
  • the present disclosure relates to an amorphous solid dispersion comprising an API and pharmaceutical compositions comprising the amorphous solid dispersion.
  • a disclosed amorphous solid dispersion comprises an API, a first acid, a second acid, and a hydrophilic high-molecular weight material.
  • a disclosed amorphous solid dispersion comprises an API, a surfactant, a non-ionic hydrophilic polymer, and optionally an adsorbent.
  • a disclosed amorphous solid dispersion comprises an adsorbent such as silica.
  • a disclosed amorphous solid dispersion comprises a protonated API, an anion of an organic acid, an anion of an inorganic acid, and a high-molecular weight material.
  • the API comprises palbociclib.
  • the API comprises neratinib.
  • the API is at least partially protonated.
  • each component of an amorphous solid dispersion such as the API, the one or more acids and the hydrophilic polymer are mixed in an amorphous state.
  • each component of an amorphous solid dispersion such as the API, the one or more acids and the hydrophilic polymer are mixed on a molecular level.
  • the API has a logP of less than 1 in unprotonated form. In some embodiments, the API has a logP of between 0.5 and 1.0 in unprotonated form. In some embodiments, the API has a logP of between 0.6 and 1.0 in unprotonated form.
  • the API has a logP of between 0.7 and 1.0 in unprotonated form. In some embodiments, the API has a logP of between 0.8 and 1.0 in unprotonated form. In some embodiments, the API has a logP of between 0.9 and 1.0 in unprotonated form. In some embodiments, the API has a pKa of about 3 to about 10. In some embodiments, the API has a logP of less than 1 in an unprotonated form and has a pKa of about 3 to about 10. In some embodiments, the API has a logP of at least about 1 in an unprotonated form and has a pKa of about 3 to about 10.
  • the API may be selected from the group consisting of palbociclib, neratinib, erlotinib, sulfacetamide, sulfachlorpyridazine, sulfadiazine, sulfadimethoxine, sulfaguanidine, sulfamerazine, sulfamethazine, sulfamethizole, sulfamethoxazole, sulfathiazole, chlortetracycline, demeclocycline, doxycycline, meclocycline, oxytetracycline, tetracycline, ciprofloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, fleroxacin, flumequine, lomefloxacin, marbofloxacin, nalidixic acid, norfloxacine, pefloxacin, pipemidic acid,
  • the first acid is an organic acid that has a pKa of at most 2.
  • a weight ratio of the second acid to the first acid is from about 0.2: 1 to about 20: 1.
  • the surfactant is selected from polymeric non-ionic surfactants and phospholipids.
  • amorphous solid dispersions described herein comprise an API, an auxiliary acid, and a hydrophilic high-molecular weight material, wherein the auxiliary acid is an organic acid, an inorganic acid, or a combination thereof.
  • the amorphous solid dispersions described here are homogenous amorphous solid dispersions.
  • a solid dispersion is a solid state solution wherein an API (or acidic API salt) and high-molecular weight material act as solute and solvent, respectively.
  • the solid dispersion can form multiple structures depending on the composition and sample processing history.
  • the API loading is lower than the equilibrium solubility of API in the high-molecular weight material, the drug is molecularly dispersed within the polymer matrix and forms a thermodynamically stable, homogeneous solution.
  • a homogenous solution is often attainable at very low API loading and/or high temperature. For higher loadings, the mixture can become a supersaturated solution and the drug precipitates out.
  • an intermediate meta-stable structure may form in which amorphous API is dispersed molecularly or dispersed as aggregates in a high-molecular weight material matrix containing the API in a non-crystalline amorphous state.
  • amorphous solid dispersions can increase apparent solubility of the API and provide superior dissolution properties, as compared to the crystalline API.
  • the amorphous solid dispersions described herein comprise APIs that are poorly soluble in free base form.
  • the poorly soluble APIs exhibit enhanced solubility when protonated to form the mono-, di-, or tri-protonated API salt (or an equilibrium mixture thereof) .
  • the solubility of the protonated API also increases.
  • an amorphous solid dispersion comprising a protonated API salt presents challenges.
  • Protonated API salts with high lattice energies tend to be driven to crystalize out of any initially formed amorphous solid dispersions due to the high stability of the crystalline state.
  • Lattice energies increase with the valency/charge or the cations and anions in the API salt. Therefore, as the protonation state of the API increases (e.g. from mono-protonated to di-protonated to tri-protic salts) , so too does the lattice energy of the API salt.
  • amorphous solid dispersions of protonated APIs are protonated by two distinct acids of specific classes and strengths.
  • amorphous solid dispersions of palbociclib comprising a first acid, wherein the first acid is an organic acid that has a pKa of at most 2; and a second acid, wherein the second acid has a pKa greater than 2; and a hydrophilic high-molecular weight material.
  • Applicant has found, surprisingly, that amorphous solid dispersions of palbociclib with the above described parameters are stable as amorphous solid dispersions and show superior bioavailability to the equivalent marketed drug product.
  • amorphous solid dispersions according to the present disclosure result in increased stability of the palbociclib active ingredient, by reducing formation of impurity byproducts.
  • an amorphous solid dispersion of the present disclosure is stored for at least 3 months, at least 98%, e.g., at least 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%of the palbociclib is retained.
  • an amorphous solid dispersion of the present disclosure is stored for at least 4 months, at least 98%, e.g., at least 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%of the palbociclib is retained.
  • an amorphous solid dispersion of the present disclosure is stored for at least 5 months, at least 98%, e.g., at least 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%of the palbociclib is retained.
  • an amorphous solid dispersion of the present disclosure is stored for at least 6 months, at least 98%, e.g., at least 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%of the palbociclib is retained.
  • an amorphous solid dispersion of the present disclosure is stored for at least 7 months, at least 98%, e.g., at least 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%of the palbociclib is retained.
  • an amorphous solid dispersion of the present disclosure is stored for at least 8 months, at least 98%, e.g., at least 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%of the palbociclib is retained.
  • an amorphous solid dispersion of the present disclosure is stored for at least 9 months, at least 98%, e.g., at least 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%of the palbociclib is retained.
  • an amorphous solid dispersion of the present disclosure is stored for at least 12 months, at least 98%, e.g., at least 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%of the palbociclib is retained.
  • an amorphous solid dispersion of the present disclosure is stored for at least 18 months, at least 98%, e.g., at least 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%of the palbociclib is retained.
  • an amorphous solid dispersion of the present disclosure is stored for at least 24 months, at least 98%, e.g., at least 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100%of the palbociclib is retained.
  • the amorphous solid dispersion of the present disclosure can be stored at room temperature, refrigerated temperature, or elevated temperature. In some embodiments, the amorphous solid dispersion is stored at 25 °C.
  • the amorphous solid dispersion is stored at 4 °C. In some embodiments, the amorphous solid dispersion is stored at 40 °C. In some embodiments, the amorphous solid dispersion is stored at 75%relative humidity (RH) . In some embodiments, the amorphous solid dispersion is stored at 40%RH. In some embodiments, the amorphous solid dispersion is stored at 60%RH.
  • Amorphous solid dispersions according to the present disclosure can result in increased stability of the palbociclib active ingredient, by reducing formation of impurity byproducts.
  • the amorphous solid dispersion contains less than about 2%, e.g., less than about 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, 0.1%, or 0.05%of a palbociclib degradation product (based on the initial weight of palbociclib) after stored for 1 month.
  • the amorphous solid dispersion contains less than about 2%, e.g., less than about 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, 0.1%, or 0.05%of a palbociclib degradation product (based on the initial weight of palbociclib) after stored for 2 months.
  • the amorphous solid dispersion contains less than about 2%, e.g., less than about 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, 0.1%, or 0.05%of a palbociclib degradation product (based on the initial weight of palbociclib) after stored for 3 months.
  • the amorphous solid dispersion contains less than about 2%, e.g., less than about 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, 0.1%, or 0.05%of a palbociclib degradation product (based on the initial weight of palbociclib) after stored for 6 months.
  • the amorphous solid dispersion contains less than about 2%, e.g., less than about 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, 0.1%, or 0.05%of a palbociclib degradation product (based on the initial weight of palbociclib) after stored for 9 months.
  • the amorphous solid dispersion contains less than about 2%, e.g., less than about 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, 0.1%, or 0.05%of a palbociclib degradation product (based on the initial weight of palbociclib) after stored for 12 months.
  • the amorphous solid dispersion contains less than about 2%, e.g., less than about 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, 0.1%, or 0.05%of a palbociclib degradation product (based on the initial weight of palbociclib) after stored for 18 months.
  • the amorphous solid dispersion contains less than about 2%, e.g., less than about 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.45%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, 0.15%, 0.1%, or 0.05%of a palbociclib degradation product (based on the initial weight of palbociclib) after stored for 24 months.
  • the amorphous solid dispersion contains no more than about 0.2%of a palbociclib degradation product (based on the initial weight of palbociclib) after stored for 1 month.
  • the amorphous solid dispersion contains no more than about 0.2%of a palbociclib degradation product (based on the initial weight of palbociclib) after stored for 3 months. In some embodiments, the amorphous solid dispersion contains no more than about 0.2%of a palbociclib degradation product (based on the initial weight of palbociclib) after stored for 6 months. In some embodiments, the amorphous solid dispersion contains no more than about 0.2%of a palbociclib degradation product (based on the initial weight of palbociclib) after stored for 9 months. In some embodiments, the amorphous solid dispersion contains no more than about 0.2%of a palbociclib degradation product (based on the initial weight of palbociclib) after stored for 12 months.
  • the amorphous solid dispersion contains no more than about 0.2%of a palbociclib degradation product (based on the initial weight of palbociclib) after stored for 18 months. In some embodiments, the amorphous solid dispersion contains no more than about 0.2%of a palbociclib degradation product (based on the initial weight of palbociclib) after stored for 24 months.
  • the palbociclib degradation product i.e., impurity
  • the palbociclib degradation product is an impurity identifiable by an HPLC method described in Example 15 or by any equivalent method.
  • the palbociclib degradation product is an impurity at relative retention time (RRT) 0.92 identifiable by an HPLC method described in Example 15, or any equivalent method.
  • the amorphous solid dispersion of the present disclosure can be stored at room temperature, refrigerated temperature, or elevated temperature. In some embodiments, the amorphous solid dispersion is stored at 25 °C. In some embodiments, the amorphous solid dispersion is stored at 4 °C. In some embodiments, the amorphous solid dispersion is stored at 40 °C. In some embodiments, the amorphous solid dispersion is stored at 75%RH. In some embodiments, the amorphous solid dispersion is stored at 40%RH. In some embodiments, the amorphous solid dispersion is stored at 60%RH.
  • Storage conditions may vary and can be, for example, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, or even longer.
  • the amorphous solid dispersion may be at a relative humidity (RH) of, e.g., 0%, 5%, 10%, 15, %, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 95%, or 100%.
  • RH relative humidity
  • an amorphous solid dispersion is stored for at least 3 months at 40°C and 75%relative humidity, at least 98%, e.g., at least 99%, or at least 99.8%of the palbociclib is retained.
  • the composition is stored for at least 3 months at 40°C and 75%relative humidity, less than about 2%, e.g., less than 1%, or less than 0.2%of a palbociclib degradation product are formed.
  • a herein described amorphous solid dispersion can have a particle size distribution.
  • a median diameter of the amorphous solid dispersion is from about 10 nm to about 500 ⁇ m. In some embodiments, a median diameter of the amorphous solid dispersion is from about 100 nm to about 300 ⁇ m. In some embodiments, a median diameter of the amorphous solid dispersion is from about 500 nm to about 50 ⁇ m. In some embodiments, a median diameter of the amorphous solid dispersion is from about 1 ⁇ m to about 20 ⁇ m. In some embodiments, a median diameter of the amorphous solid dispersion is from about 1 ⁇ m to about 15 ⁇ m.
  • D10, D50, and D90 are used to describe a particle size distribution.
  • D50 value the median diameter
  • D90 refers to a diameter value where 10%of the particle population (by volume) have a diameter larger than and 90%of the particle population have a diameter smaller than the D90 value.
  • D10 refers to a diameter value where 90%of the particle population (by volume) have a diameter larger than and 10%of the particle population have a diameter smaller than the D10 value.
  • Particle size and size distribution can be measured by commercially available light scattering particle size analyzers, such as Malvern Particle Size Analyzer 3000.
  • a herein described amorphous solid dispersion has a particle size distribution with a D50 value of about 100 nm to about 100 ⁇ m, or any ranges therebetween.
  • the D50 value is about 100 nm, about 500 nm, about 1 ⁇ m, about 5 ⁇ m, about 10 ⁇ m, about 15 ⁇ m, about 20 ⁇ m, about 25 ⁇ m, about 30 ⁇ m, about 40 ⁇ m, about 50 ⁇ m, about 60 ⁇ m, about 75 ⁇ m, or about 100 ⁇ m.
  • the D50 value is at least about 100 nm, at least about 500 nm, at least about 1 ⁇ m, at least about 5 ⁇ m, at least about 10 ⁇ m, at least about 15 ⁇ m, or at least about 20 ⁇ m. In some embodiments, the D50 value is at most about 500 nm, at most about 1 ⁇ m, at most about 5 ⁇ m, at most about 10 ⁇ m, at most about 15 ⁇ m, at most about 20 ⁇ m, at most about 50 ⁇ m, or at most about 100 ⁇ m.
  • the D50 value is in a range of from about 500 nm, about 1 ⁇ m, about 2 ⁇ m, about 3 ⁇ m, about 4 ⁇ m, or about 5 ⁇ m to about 8 ⁇ m, about 10 ⁇ m, about 15 ⁇ m, about 20 ⁇ m, or about 30 ⁇ m. In some embodiments, the D50 value is about 1 ⁇ m to about 20 ⁇ m, or any ranges therebetween.
  • a herein described amorphous solid dispersion has a particle size distribution with a D90 value of about 100 nm to about 500 ⁇ m, or any ranges therebetween.
  • the D90 value is about 100 nm, about 500 nm, about 1 ⁇ m, about 5 ⁇ m, about 10 ⁇ m, about 15 ⁇ m, about 20 ⁇ m, about 25 ⁇ m, about 30 ⁇ m, about 40 ⁇ m, about 50 ⁇ m, about 60 ⁇ m, about 75 ⁇ m, about 100 ⁇ m, about 200 ⁇ m, or about 500 ⁇ m.
  • the D90 value is at least about 100 nm, at least about 500 nm, at least about 1 ⁇ m, at least about 5 ⁇ m, at least about 10 ⁇ m, at least about 15 ⁇ m, or at least about 20 ⁇ m. In some embodiments, the D90 value is at most about 500 nm, at most about 1 ⁇ m, at most about 5 ⁇ m, at most about 10 ⁇ m, at most about 15 ⁇ m, at most about 20 ⁇ m, at most about 50 ⁇ m, at most about 100 ⁇ m, at most about 200 ⁇ m, or at most about 500 ⁇ m.
  • the D90 value is in a range of from about 500 nm, about 1 ⁇ m, about 2 ⁇ m, about 3 ⁇ m, about 4 ⁇ m, or about 5 ⁇ m to about 10 ⁇ m, about 15 ⁇ m, about 20 ⁇ m, or about 50 ⁇ m. In some embodiments, the D90 value is about 1 ⁇ m to about 50 ⁇ m, or any ranges therebetween.
  • a herein described amorphous solid dispersion has a glass transition temperature (Tg) higher than 20 °C. In some embodiments, the amorphous solid dispersion has a Tg of at least 25 °C, at least 30 °C, at least 40 °C, at least 50 °C, at least 60 °C, at least 70 °C, at least 80 °C, at least 90 °C, or at least 100 °C. In some embodiments, a herein described amorphous solid dispersion has a Tg of at least 50 °C.
  • amorphous solid dispersions and pharmaceutical compositions comprising an API.
  • the API has a limited or low solubility in water at neutral pH.
  • the API is lipophilic.
  • the API comprises a free base of the API, a salt of the API, a solvate of the API, or a combination thereof.
  • the API comprises at least partially protonated API.
  • the protonated API is a salt resulting from the reaction of the free base API and an acid.
  • the API is at least partially protonated. In some embodiments, an at least partially protonated API contains about 1%or more of pronated API. In some embodiments, an at least partially protonated API contains about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of pronated API. In some embodiments, the at least partially protonated API includes an API which is mono-protonated, di-protonated, or tri-protonated.
  • At least partially protonated API includes an API which is in an equilibrium among one or more of non-protonation, mono-protonation, di-protonation and tri-protonation states. In some embodiments, an at least partially protonated API includes an API which is in an equilibrium between non-protonation and mono-protonation states. In some embodiments, an at least partially protonated API comprises mono-protonated, di-protonated, and/or tri-protonated API.
  • Protonated API can refer to the cationic portion of a salt that is formed when an acid is added to a basic API.
  • a protonated API is mono-protonated, di-protonated, or tri-protonated.
  • a protonated API is in an equilibrium among one or more of non-protonation, mono-protonation, di-protonation and tri-protonation states.
  • a protonated API is in an equilibrium between non-protonation, mono-protonation, and di-protonation states.
  • a protonated API is in an equilibrium between non-protonation and mono-protonation states.
  • a protonated API comprises mono-protonated, di-protonated, and/or tri-protonated API.
  • a protonated API is an API salt.
  • an API salt is monovalent or divalent.
  • an API salt is a mixture of a monovalent API salt and divalent API salt.
  • a monovalent salt is a salt in which the API cation or has a +1 charge. In instances wherein the API is singly protonated and has distinct conjugate acids, the salt is monovalent.
  • a salt of monoprotonated API “ [HAPI] + ” with substoichiometric amounts of conjugate acids tartrate [C 4 H 5 O 6 ] - and chloride [Cl] - is a monovalent salt [HAPI] [C 4 H 5 O 6 ] 0.5 [Cl] 0.5 .
  • Additional example [HAPI] [SO 4 ] 0.5 is also a monovalent salt.
  • a divalent salt is a salt in which the cation has a +2 charge.
  • Non limiting examples include an API salt which is doubly protonated and has a conjugate acid with a -2 charge (e.g. [H 2 API] [SO 4 ] ) .
  • An additional example is an API salt which is doubly protonated and has two conjugate acids with a -1 charge [H 2 API] [C 4 H 5 O 6 ] [Cl] .
  • a trivalent salt is a salt in which the API cation has a +3 charge and is triply protonated.
  • the acid dissociation constant (K a ) is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction known as dissociation in the context of acid–base reactions. In aqueous solution, the equilibrium of acid dissociation can be written symbolically as:
  • HA is a generic acid that dissociates into A-, known as the conjugate base of the acid and a hydrogen ion which combines with a water molecule to make a hydronium ion.
  • the chemical species HA, H 2 O, A-and H 3 O + are said to be in equilibrium when their concentrations (written below in square brackets) do not change with the passing of time.
  • the dissociation constant is usually defined for a simplified reaction equation in which the solvent H 2 O is ignored:
  • the protonated API is a weak acid, as determined by the pK a of the protonated API measured in water. In some embodiments, the protonated API is a weak acid, as determined by the calculated pK a of the protonated API. In some embodiments, the API has a pK a of about -2 to about 12, or any ranges therebetween. In some embodiments, the API has a pKa of about 1 to about 12. In some embodiments, the API has a pKa of about 3 to about 8.
  • the API has a pK a of about 1 to about 2, about 1 to about 3, about 1 to about 4, about 1 to about 5, about 1 to about 6, about 1 to about 7, about 1 to about 8, about 1 to about 9, about 1 to about 10, about 1 to about 11, about 1 to about 12, about 2 to about 3, about 2 to about 4, about 2 to about 5, about 2 to about 6, about 2 to about 7, about 2 to about 8, about 2 to about 9, about 2 to about 10, about 2 to about 11, about 2 to about 12, about 3 to about 4, about 3 to about 5, about 3 to about 6, about 3 to about 7, about 3 to about 8, about 3 to about 9, about 3 to about 10, about 3 to about 11, about 3 to about 12, about 4 to about 5, about 4 to about 6, about 4 to about 7, about 4 to about 8, about 4 to about 9, about 4 to about 10, about 4 to about 11, about 4 to about 12, about 5 to about 6, about 5 to about 7, about 5 to about 8, about 5 to about 9, about 5 to about 10, about 5 to about 11, about 5 to about 12, about 6 to about 7, about 8, about 6 to about 8, about 6 to about 9, about
  • the API has a pK a of at least about -2, at least about -1, at least about 0, at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, or at least about 10.
  • the API has a pK a of at most about 12, at most about 11, at most about 10, at most about 9, at most about 8, at most about 7, at most about 6, at most about 5, at most about 4, or at most about 3.
  • Exemplary small molecule APIs with calculated pK a of about -2 to about 12 include, without limitation, those APIs listed in Table A.
  • Techniques for measuring the pK a of the APIs in Table A are known in the art, such as those described in Babic, S.; Horvat, J.M.; Pavlovic, D.M.; Kastelan-Macan, M.; Trends in Anal. Chem.; 26, 11, 2007.
  • the pKa values of the APIs can be determined by potentiometric titration, by spectrophotometric methods, by NMR titration, by liquid chromatography, by capillary electrophoresis (CE) , or by computational methods.
  • analysis methods used to derive pKa values from titration curves in a potentiometric titration include Grans plot, second-derivative ( ⁇ 2 pH/ ⁇ V 2 ) , and least-squares non-linear regression.
  • the partition-coefficient (P) as referenced herein is a ratio of concentrations of a compound between two immiscible solvent phases at equilibrium. Most commonly, one of the solvents is water and the other is hydrophobic, typically1-octanol.
  • the logarithm of the ratio is log P, as shown below (conventionally the lipophilic phase is the numerator and hydrophilic phase is the denominator) . Accordingly, log P is a measure of lipophilicity or hydrophobicity.
  • Partition coefficients can be measured experimentally or estimated via calculation.
  • Various methods for calculating (or predicting) log P have been developed, typically by fitting calculated log P values with experimentally measured log P values for training sets of thousands of molecules, mostly drug-like. To distinguish from a measured log P, a calculated log P is sometimes written as clog P.
  • log P refers to an experimental log P value. Methods of experimentally determining log P values are known in the art, for example, see J.M. Pallicer, C. Calvet, A. Port, M. Rosés, C. Ràfols, E. Bosch, Journal of Chromatography A 1240 (2012) 113-122, the contents of which are incorporated by their entirety herein.
  • the API is lipophilic. In some embodiments, the API free base is lipophilic. In some embodiments, the API has a log P of at least about 1, at least about 2, at least about 3, at least about 4, or at least about 5 in a free base or unprotonated form. In some embodiments, the API has a log P of at least about 0.8. In some embodiments, the API has a log P of at least about 0.9.
  • a ratio of a solubility of the protonated API to a solubility of the API as a free base is at least 1.5: 1, at least 2: 1, at least 3: 1, at least 5: 1, at least 10: 1, at least 20: 1, at least 50: 1, at least 100: 1 or at least 200: 1 in water. In some embodiments, a ratio of a solubility of the protonated API to a solubility of the API as a free base is at least 10: 1.
  • the API has a low solubility at a pH of about 6-8. In some embodiments, the API has a solubility of less than 10 mg/ml, less than 1.0 mg/ml, less than 0.5 mg/ml, less than 0.1 mg/ml, less than 0.05 mg/ml, less than 0.04 mg/ml, less than 0.03 mg/ml, less than 0.02 mg/ml, less than 0.01 mg/ml, less than 0.002 mg/ml, or less than 0.001 mg/ml in an aqueous solution with a pH of between about 6-8. In some embodiments, the API has a higher solubility at a pH lower than 6.
  • the API has a solubility of at least 0.02 mg/ml, at least 0.05 mg/ml, at least 0.1 mg/ml, at least 0.2 mg/ml, at least 0.5 mg/ml, at least 0.7 mg/ml, at least 1 mg/ml, at least 5 mg/ml, or at least 10 mg/ml in an aqueous solution with a pH lower than 6.
  • the API has a low solubility at a pH of 5 or higher. In some embodiments, the API has a solubility of less than 10 mg/ml, less than 1.0 mg/ml, less than 0.5 mg/ml, less than 0.1 mg/ml, less than 0.05 mg/ml, less than 0.04 mg/ml, less than 0.03 mg/ml, less than 0.02 mg/ml, less than 0.01 mg/ml, or less than 0.001 mg/ml in an aqueous solution with a pH of 5 or higher. In some embodiments, the API has a higher solubility at a pH of 4 or lower.
  • the API has a solubility of at least 0.02 mg/ml, at least 0.05 mg/ml, at least 0.1 mg/ml, at least 0.2 mg/ml, at least 0.5 mg/ml, at least 0.7 mg/ml, at least 1 mg/ml, at least 5 mg/ml, or at least 10 mg/ml in an aqueous solution with a pH of 4 or lower.
  • an amorphous solid dispersion that comprises: (a) an active pharmaceutical ingredient (API) , wherein the API comprises a compound of Formula (I) ,
  • - is a single bond or a double bond
  • R 1 is C 1 -C 6 alkyl
  • R 3 is C 1 -C 8 alkoxy, C 3 -C 7 cycloalkyl, or C 3 -C 7 -heterocyclyl;
  • R 2 and R 4 are each independently hydrogen, halogen, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 hydroxyalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, nitrile, nitro, -OR 10 , -SR 10 , -NR 10 R 11 , -N (O) R 10 R 11 , -P (O) (OR 10 ) (OR 11 ) , - (CR 10 R 11 ) m NR 12 R 13 , -COR 10 , - (CR 10 R 11 ) m C (O) R 12 , -CO 2 R 10 , -CONR 10 R 11 , -C (O) NR 10 SO 2 R 11
  • each of R 5 , R 6 , and R 7 is independently hydrogen, halogen, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 1 -C 8 alkoxy, -C 1 -C 8 alkoxyalkyl, -CN, -NO 2 , -OR 10 , -NR 10 R 11 , -CO 2 R 10 , -COR 10 , -S (O) n R 10 , -CONR 10 R 11 , -NR 10 COR 11 , -NR 10 SO 2 R 11 , -SO 2 NR 10 R 11 , or -P (O) (OR 10 ) (OR 11 ) ;
  • each of R 10 , R 11 , R 12 and R 13 is independently hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • - m is 0, 1, 2, 3, 4, 5, or 6;
  • - n 0, 1 or 2;
  • API is at least partially protonated
  • the amorphous solid dispersion further comprises and optional adsorbent.
  • an amorphous solid dispersion that comprises: (a) an active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof, wherein the API comprises a compound of Formula (I) ; (b) a surfactant, wherein the surfactant is selected from polymeric non-ionic surfactants and phospholipids; (c) a non-ionic hydrophilic polymer; and (d) optionally an adsorbent.
  • the API, or a salt or solvate thereof comprises about 5%to about 70%of a total weight of the amorphous solid dispersion.
  • the surfactant is a polymeric non-ionic surfactant.
  • the polymeric non-ionic surfactant comprises a block copolymer of polyethylene glycol and polypropylene glycol. In some embodiments, the polymeric non-ionic surfactant is Poloxamer 188. In some embodiments, the surfactant comprises one or more phospholipids. In some embodiments, the surfactant comprises one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, plasmalogen, sphingomyelin, and phosphatidic acid. In some embodiments, the surfactant comprises lecithin.
  • the surfactant comprises about 5%to about 70%of a total weight of the amorphous solid dispersion. In some embodiments, a weight ratio of the API or a salt or solvate thereof to the surfactant is from about 10: 1 to about 1: 10.
  • each of R 5 , R 6 , and R 7 is independently hydrogen, halogen, or C 1 -C 6 alkyl. In some embodiments, each of R 5 , R 6 , and R 7 is hydrogen. In some embodiments, R 1 is methyl.
  • R 2 is hydrogen, halogen, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 hydroxyalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, nitrile, nitro, -COR 10 or OR 10 .
  • R 2 is C 3 -C 7 cycloalkyl.
  • R 2 is COR 10 .
  • R 2 is - (CO) CH 3 .
  • R 3 is C 3 -C 7 cycloalkyl. In some embodiments, R 3 is cyclopentyl. In some embodiments, R 4 is hydrogen, halogen, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 hydroxyalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, nitrile, nitro, or OR 10 . In some embodiments, R 4 is C 3 -C 7 cycloalkyl.
  • R 4 is C 3 -C 7 heterocycloalkyl. In some embodiments, R 4 is 6-membered heterocycloalkyl containing 1 or 2 ring nitrogen atoms. In some embodiments, R 4 is piperazin-1-yl. In some embodiments, each of R 10 , R 11 , R 12 and R 13 is independently hydrogen or C 1 -C 8 alkyl. In some embodiments, each of R 10 , R 11 , R 12 and R 13 is independently hydrogen or methyl.
  • the API of Formula (I) is at least partially protonated. In some embodiments, the API of Formula (I) is palbociclib or a salt or solvate thereof.
  • Palbociclib is a selective inhibitor of CDK4/6 and its chemical name is 6-acetyl-8-cycic-5-methyl-2- [ [5- (piperazine-1-based) pyridine-2-base] -8H-pyridine and [2, pyrimidine + ketone, belonging to the category of pyridine and pyrimidine.
  • the IC50 (the concentration when the tumor cells account for 50%of total cells) of selective inhibitor CDK4 and CDK6 is 11nmol/L and 15nmol/L, respectively, while the IC50 of CDK2, CDK1, and CDK5 was more than 10nmol/L.
  • a pharmaceutical composition and/or an amorphous solid dispersion provided herein comprises an API that is palbociclib.
  • Conjugate acids of palbociclib have a pK a of 3.9 and 7.4 in water.
  • the protonated API is protonated palbociclib.
  • the API comprises monoprotonated palbociclib.
  • the API comprises diprotonated palbociclib.
  • the API comprises palbociclib free base, monoprotonated palbociclib, diprotonated palbociclib, or any combination thereof.
  • the API comprises monoprotonated palbociclib, diprotonated palbociclib, or both.
  • the API comprises palbociclib free base, monoprotonated palbociclib, and/or diprotonated palbociclib, in an equilibrium state. In some embodiments, the API comprises palbociclib free base and monoprotonated palbociclib, in an equilibrium state. In some embodiments, the palbociclib is protonated on the secondary piperazine nitrogen. In some embodiments, the palbociclib is protonated on the pyridine nitrogen, the secondary piperazine nitrogen, or both.
  • an amorphous solid dispersion that comprises: a) an active pharmaceutical ingredient (API) , wherein the API comprises a compound of Formula (II) ,
  • R 1 is halogen
  • R 2 is a pyridinyl, thiophene, pyrimidine, thiazole, or phenyl, each of which is optionally substituted with up to three substituents;
  • - R 3 is -O-or -S-;
  • R 4 is C 1-3 alkyl or C 1-3 heteroalkyl
  • R 5 is ethyl or methyl
  • - n is 0 or 1;
  • R 1 is chlorine.
  • R 2 is pyridinyl.
  • R 3 is -O-.
  • R 4 is methyl.
  • R 5 is ethyl.
  • n is 1.
  • the compound of Formula (II) is neratinib
  • the compound of formula (II) comprises a maleate salt. In some embodiments, the compound of formula (II) is neratinib maleate.
  • the API of Formula (I) is at least partially protonated. In some embodiments, the API of Formula (II) is neratinib or a salt or solvate thereof.
  • an amorphous solid dispersion that comprises: (a) an active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof, wherein the API comprises a compound of Formula (II) ; (b) a surfactant, wherein the surfactant is selected from polymeric non-ionic surfactants and phospholipids; (c) a non-ionic hydrophilic polymer; and (d) optionally an adsorbent.
  • Neratinib is a kinase inhibitor indicated for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.
  • Neratinib is a member of the 4-anilino quinolidine class of protein kinase inhibitors.
  • the molecular formula for neratinib maleate is C 30 H 29 ClN 6 O 3 ⁇ C 4 H 4 O 4 and the molecular weight is 673.11 Daltons.
  • Neratinib is a kinase inhibitor that irreversibly binds to Epidermal Growth Factor Receptor (EGFR) , Human Epidermal Growth Factor Receptor 2 (HER2) , and HER4.
  • EGFR Epidermal Growth Factor Receptor
  • HER2 Human Epidermal Growth Factor Receptor 2
  • neratinib reduces EGFR and HER2 autophosphorylation, downstream MAPK and AKT signaling pathways, and showed antitumor activity in EGFR and/or HER2 expressing carcinoma cell lines.
  • Neratinib human metabolites M3, M6, M7 and M11 inhibited the activity of EGFR, HER2 and HER4 in vitro.
  • oral administration of neratinib inhibited tumor growth in mouse xenograft models with tumor cell lines expressing HER2 and EGFR.
  • a pharmaceutical composition and/or an amorphous solid dispersion provided herein comprises an API that is neratinib.
  • Conjugate acids of neratinib such as neratinib maleate, have a pK a of 4.66 and 7.65 in water.
  • the protonated API is protonated neratinib.
  • the API comprises monoprotonated neratinib.
  • the API comprises diprotonated neratinib.
  • the API comprises neratinib free base, monoprotonated neratinib, diprotonated neratinib, or any combination thereof.
  • the API comprises monoprotonated neratinib, diprotonated neratinib, or both. In some embodiments, the API comprises neratinib free base, monoprotonated neratinib, and/or diprotonated neratinib, in an equilibrium state. In some embodiments, the API comprises neratinib free base and monoprotonated neratinib, in an equilibrium state.
  • a described amorphous solid dispersion comprises an API that is at least partially protonated.
  • the amorphous solid dispersion comprises a protonated API, an anion of an organic or an inorganic acid, and a high-molecular weight material.
  • a described amorphous solid dispersion comprises a salt of the API, wherein the cation of the salt is the protonated API.
  • the salt of the API is a reaction product of the API free base (or a salt thereof) with an acid.
  • the amorphous solid dispersion comprises a salt of the API, wherein the salt is formed in situ.
  • the amorphous solid dispersion comprises a salt of palbociclib, wherein the salt is a reaction product of palbociclib free base with an acid.
  • the at least partially protonated API is a reaction product of a first acid with a freebase of the API.
  • the API comprises at least partially protonated palbociclib.
  • the partially protonated palbociclib is a reaction product of a first acid with palbociclib free base or a salt thereof.
  • the amorphous solid dispersion comprises a mesylate salt of the API such as palbociclib mesylate.
  • the mesylate salt of the API (e.g., palbociclib mesylate) is formed in situ.
  • the amorphous solid dispersion comprises a salt of neratinib, wherein the salt is a reaction product of neratinib free base with an acid.
  • the at least partially protonated API is a reaction product of a first acid with a freebase of the API.
  • the API comprises at least partially protonated neratinib.
  • the partially protonated neratinib is a reaction product of a first acid with neratinib free base or a salt thereof.
  • the amorphous solid dispersion comprises a maleate salt of the API such as neratinib maleate.
  • the maleate salt of the API e.g., neratinib maleate
  • the maleate salt of the API is formed in situ.
  • an amorphous solid dispersion comprises the free base of an API, a first acid, a second acid, and a hydrophilic-high molecular weight polymer.
  • Such amorphous solid dispersions are interchangeable with an amorphous solid dispersion comprising an acidic salt of an API, a second acid, and a hydrophilic-high molecular weight polymer, wherein the acidic salt of the API is formed from the reaction of the free base API and the first acid.
  • the acidic salt of the API is generated in situ.
  • the acidic salt of the API is in the solid state and is dissolved during the formation of the amorphous solid dispersion.
  • an amorphous solid dispersion disclosed herein can comprise a salt of an API.
  • an amorphous solid dispersion comprises at least partially protonated API that comprises a cation present in a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include, but are not limited to, metal salts, such as sodium salts, potassium salts, and lithium salts; alkaline earth metals, such as calcium salts, magnesium salts, and the like; organic amine salts, such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N, N'-dibenzylethylenediamine salts, and the like; inorganic acid salts such as hydrochloride salts, hydrobromide salts, sulfate salts, phosphate salts, and the like; organic acid salts such as formate salts, acetate salts, trifluoroacetate salts, maleate salts
  • Pharmaceutically acceptable salts further include, without limitation, bitartrate, bitartrate hydrate, hydrochloride, p-toluenesulfonate, phosphate, sulfate, trifluoroacetate, bitartrate hemipentahydrate, pentafluoropropionate, hydrobromide, mucate, oleate, phosphate dibasic, phosphate monobasic, acetate trihydrate, bis (heptafuorobutyrate) , bis(pentaflu oropropionate) , bis (pyridine carboxylate) , bis (trifluoroacetate) , chlorhydrate, and sulfate pentahydrate.
  • salts include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4, 4-diaminostilbene-2, 2-disulfonate) , benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, camphorsulfonate, camsylate, carbonate, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, mal
  • the salt of the API can be formed by reacting the API free base with an acid, such as an acid described in the present disclosure.
  • the API is palbociclib or a pharmaceutically acceptable salt thereof.
  • the API is neratinib or a pharmaceutically acceptable salt thereof, such as neratinib maleate.
  • the API is one listed in Table A, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition and/or an amorphous solid dispersion provided herein comprises an API (such as palbociclib or neratinib) in an amount of 10 mg to 1000 mg. In some embodiments, the API is present in an amount of 20 mg to 500 mg.
  • a pharmaceutical composition and/or an amorphous solid dispersion provided herein comprises an API (such as palbociclib or neratinib) in an amount of from about 1 mg to about 500 mg, from about 10 mg to about 400 mg, from about 10 mg to about 250 mg, from about 5 mg to about 250 mg, from about 25 mg to about 250 mg, from about 25 mg to about 200 mg, from about 50 mg to about 200 mg, from about 50 mg to about 150 mg, from about 75 mg to about 150 mg, from about 100 mg to about 150 mg, from about 125 mg to about 150 mg, from about 75 mg to about 125 mg, from about 100 mg to about 125 mg, from about 75 mg to about 125 mg, from about 50 mg to about 125 mg, from about 25 mg to about 125 mg, from about 75 mg to about 100 mg, from about 50 mg to about 125 mg, from about 25 mg to about 125 mg, from about 75 mg to about 100 mg, from about 50 mg to about 125 mg, from about 25 mg to about 125 mg, from about 75 mg to
  • a pharmaceutical composition and/or an amorphous solid dispersion comprises an API in an amount of at least 10 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 110 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 140 mg, at least 150 mg, at least 160 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 190 mg, or at least 200 mg.
  • a pharmaceutical composition described herein comprises an API in an amount of from about 5 mg to about 200 mg.
  • a pharmaceutical composition and/or an amorphous solid dispersion that comprises an API in an amount of at most 1000 mg.
  • the API is present in an amount of at most 750 mg, at most 500 mg, at most 400 mg, at most 300 mg, at most 250 mg, at most 225 mg, at most 200 mg, at most 175 mg, at most 150 mg, at most 125 mg, at most 100 mg, at most 90 mg, at most 80 mg, at most 75 mg, at most 60 mg, at most 55 mg, at most 50 mg, at most 25 mg, or at most 10 mg.
  • the API is in a free base form.
  • the API is protonated or partially protonated.
  • the API is in a salt or solvate form. In some embodiments the API is palbociclib or a pharmaceutically acceptable salt or solvate thereof. In some embodiments the API is neratinib or a pharmaceutically acceptable salt thereof, such as neratinib maleate. In some embodiments, the API is one listed in Table A, or a pharmaceutically acceptable salt or solvate thereof.
  • a pharmaceutical composition and/or an amorphous solid dispersion provided herein comprises an API (such as palbociclib or neratinib) that is present in an amount of from about 1.0 mg to about 1000 mg, including but not limited to about 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29
  • API such
  • the API is in a free base form. In some embodiments, the API is protonated or partially protonated. In some embodiments, the API is in a salt or solvate form. In some embodiments, the API is one listed in Table A, or a pharmaceutically acceptable salt or solvate thereof.
  • a pharmaceutical composition and/or an amorphous solid dispersion provided herein comprises palbociclib.
  • a pharmaceutical composition described herein comprises palbociclib or a salt or solvate thereof in an amount of equivalent to 50 mg of palbociclib free base.
  • a pharmaceutical composition described herein comprises palbociclib or a salt or solvate thereof in an amount of equivalent to 75 mg of palbociclib free base.
  • a pharmaceutical composition described herein comprises palbociclib or a salt or solvate thereof in an amount of equivalent to 100 mg of palbociclib free base.
  • a pharmaceutical composition described herein comprises palbociclib or a salt or solvate thereof in an amount of equivalent to 125 mg of palbociclib free base. In some embodiments, a pharmaceutical composition described herein comprises palbociclib or a salt or solvate thereof in an amount of equivalent to about 75 to about 125 mg of palbociclib free base. In some embodiments, a pharmaceutical composition described herein comprises palbociclib or a salt or solvate thereof in an amount of equivalent to about 25 to about 500 mg of palbociclib free base, or any ranges therebetween. In some embodiments, the palbociclib is at least partially protonated.
  • the pharmaceutical composition comprises palbociclib acetate, palbociclib chloride, palbociclib tartrate, palbociclib mesylate, or a combination thereof. In some embodiments, the pharmaceutical composition comprises palbociclib tartrate, palbociclib mesylate, or both.
  • a pharmaceutical composition and/or an amorphous solid dispersion provided herein comprises neratinib.
  • a pharmaceutical composition described herein comprises neratinib or a salt or solvate thereof in an amount of equivalent to 20 mg of neratinib free base.
  • a pharmaceutical composition described herein comprises neratinib or a salt or solvate thereof in an amount of equivalent to 40 mg of neratinib free base.
  • a pharmaceutical composition described herein comprises neratinib or a salt or solvate thereof in an amount of equivalent to 60 mg of neratinib free base.
  • a pharmaceutical composition described herein comprises neratinib or a salt or solvate thereof in an amount of equivalent to 100 mg of neratinib free base. In some embodiments, a pharmaceutical composition described herein comprises neratinib or a salt or solvate thereof in an amount of equivalent to about 20 to about 100 mg of neratinib free base. In some embodiments, a pharmaceutical composition described herein comprises neratinib or a salt or solvate thereof in an amount of equivalent to about 30 to about 50 mg of neratinib free base, or any ranges therebetween. In some embodiments, the neratinib is at least partially protonated.
  • the pharmaceutical composition comprises neratinib maleate, neratinib malate, neratinib tartrate, neratinib mesylate, or a combination thereof. In some embodiments, the pharmaceutical composition comprises neratinib maleate, neratinib mesylate, or both.
  • a pharmaceutical composition and/or an amorphous solid dispersion provided herein comprises an API (such as palbociclib or neratinib) in an amount of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, or about 70%of the total weight of the composition.
  • an API such as palbociclib or neratinib
  • a pharmaceutical composition and/or an amorphous solid dispersion provided herein comprises an API (such as palbociclib or neratinib) in an amount of about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50%of the total weight of the composition.
  • an API such as palbociclib or neratinib
  • a pharmaceutical composition and/or an amorphous solid dispersion provided herein comprises an API (such as palbociclib or neratinib) in an amount of from about 0.1%to about 99%, from about 0.1%to about 80%, about 0.1%to about 60%, from about 0.1%to about 40%, from about 0.1%to about 20%, from about 0.1%to about 10%, from about 0.1%to about 1%, from about 20%to about 99%, from about 20%to about 80%, from about 20%to about 60%, from about 20%to about 40%, from about 25%to about 45%, from about 25%to about 50%, from about 25%to about 60%, from about 25%to about 75%, from about 30%to about 99%, from about 30%to about 80%, from about 30%to about 60%, from about 30%to about 50%, from about 30%to about 40%, from about 40%to about 99%, from about 40%to about 80%, from about 40%to about 60%, from about 40%to about 50%, or from about 40%to about 45%of the total weight of the composition.
  • an API such as palbociclib or
  • the API is in a free base form. In some embodiments, the API is protonated or partially protonated. In some embodiments, the API is in a salt or solvate form. In some embodiments the API is palbociclib or a pharmaceutically acceptable salt or solvate thereof. In some embodiments the API is neratinib or a pharmaceutically acceptable salt thereof, such as neratinib maleate. In some embodiments, the API is one listed in Table A, or a pharmaceutically acceptable salt or solvate thereof.
  • an amorphous solid dispersion comprising an API and one or more acids.
  • a pharmaceutical composition comprising an API and one or more acids.
  • the amorphous solid dispersion comprises an API, one or more acids, and a hydrophilic high-molecular weight material.
  • the amorphous solid dispersion comprises an API, a first acid, a second acid, and a hydrophilic high-molecular weight material.
  • the API is at least partially protonated.
  • an amorphous solid dispersion and/or a pharmaceutical composition disclosed herein comprises one or more organic acids.
  • the organic acid has a pKa smaller than 1.
  • the organic acid has a pKa that is at most 2.
  • the organic acid has a pKa that is at most 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 4.0, or 5.0.
  • the organic acid is completely ionized.
  • the organic acid is partially ionized.
  • the one or more organic acids comprise one or more of acetic acid, acrylic acid, adipic acid, alginic acid, amino acids, ascorbic acid, benzoic acid, benzenesulfonic acid, butyric acid, carbonic acid, citric acid, formic acid, fumaric acid, gluconic acid, isoascorbic acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, fluorinated acids, trifluoromethanesulfonic acid, trifluoroacetic acid, oxalic acid, propionic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, aliphatic sulfonic acids (e.g., methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic
  • the one or more organic acids comprise methanesulfonic acid, tartaric acid, or both. In some embodiments, the one or more organic acids comprise methanesulfonic acid and tartaric acid. In some embodiments, the one or more organic acids excludes acetic acid.
  • the amorphous solid dispersion comprises an API, one or more acids, and a hydrophilic high-molecular weight material.
  • one or more acids comprises a first acid with a pKa of at most 2 and a second acid with a pKa of greater than 2.
  • the first acid is an organic acid.
  • the first acid is oxalic acid, maleic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, an aliphatic sulfonic acid, or an aromatic sulfonic acid.
  • the aliphatic sulfonic acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanesulfonic acid, butanesulfonic acid, benzylsulfonic acid.
  • the aromatic sulfonic acid is benzenesulfonic acid, tolylsulfonic acid, or naphthalenesulfonic acid.
  • the first acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanesulfonic acid, butanesulfonic acid, benzylsulfonic acid, benzenesulfonic acid, tolylsulfonic acid, or naphthalenesulfonic acid.
  • the second acid is tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, or acetic acid.
  • the amorphous solid dispersion comprises a salt of the API, which is formed between the API free base and the first acid.
  • the one or more organic acids are present in the amorphous solid dispersion and/or in the pharmaceutical composition in an amount of from about 0.1%to about 99%by weight of the total composition. In some embodiments, the one or more organic acids are present in the amorphous solid dispersion and/or in the pharmaceutical composition in an amount of from about 1%to about 80%, from about 1%to about 60%, from about 1%to about 50%, from about 1%to about 25%, from about 1%to about 10%, from about 1%to about 5%, from about 10%to about 80%, from about 10%to about 60%, from about 10%to about 50%, from about 20%to about 80%, from about 20%to about 60%, from about 20%to about 50%, from about 30%to about 80%, from about 30%to about 60%, from about 30%to about 50%, or from about 30%to about 40%by weight of the total composition.
  • the one or more organic acids are present in the amorphous solid dispersion and/or in the pharmaceutical composition in an amount of about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, or about 45%by weight of the total composition.
  • the one or more organic acids comprise tartaric acid.
  • the one or more organic acids comprise methanesulfonic acid.
  • the one or more organic acids are present in the amorphous solid dispersion and/or in the pharmaceutical composition in an amount of about 1.0 mg to about 1000 mg, including but not limited to about 5.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg,
  • the one or more organic acids are present in the amorphous solid dispersion and/or in the pharmaceutical composition in an amount of 1 mg to 500 mg. In some embodiments, the one or more organic acids are present in an amount of from about from about 10 mg to about 400 mg, 20 mg to about 300 mg, from about 25 mg to about 200 mg, from about 50 mg to about 150 mg, from about 75 mg to about 125 mg, from about 75 mg to about 100 mg, from about 100 mg to about 125 mg, from about 1 mg to about 200 mg, or from about 50 mg to about 200 mg. In some embodiments, the one or more organic acids are present in an amount of 25 mg to 250 mg. In some embodiments, the one or more organic acids are present in an amount of 150 mg to 250 mg.
  • the one or more organic acids are present in an amount of 50 mg to 150 mg. In some embodiments, the one or more organic acids are present in an amount of 75 mg to 150 mg. In some embodiments, the one or more organic acids are present in an amount of 75 mg to 125 mg. In some embodiments, the one or more organic acids are present in an amount of 90 mg to 120 mg. In some embodiments, the one or more organic acids are present in an amount of 100 mg to 120 mg. In some embodiments, the one or more organic acids are present in an amount of 110 mg to 120 mg. In some embodiments, the one or more organic acids are present in an amount of 110 mg to 115 mg. In some embodiments, the one or more organic acids are present in an amount of 150 mg to 200 mg. In some embodiments, the one or more organic acids are present in an amount of 50 mg to 200 mg.
  • the one or more organic acids are present in a molar ratio to the API of greater than 0.5: 1, greater than 1: 1, greater than 1.5: 1, greater than 2: 1, greater than 2.5: 1, or greater than 3: 1. In some embodiments, the one or more organic acids are present in a molar ratio to the API of about 0.5: 1 to about 1: 1, about 0.5: 1 to about 1.5: 1, about 0.5: 1 to about 2: 1, about 0.5: 1 to about 2.5: 1, about 0.5: 1 to about 3: 1, about 1: 1 to about 1.5: 1, about 1: 1 to about 2: 1, about 1: 1 to about 2.5: 1, about 1: 1 to about 3: 1, about 1.5: 1 to about 2: 1, about 1.5: 1 to about 2.5: 1, about 1.5: 1 to about 3: 1, about 2: 1 to about 2.5: 1, about 2: 1 to about 3: 1, or about 2.5: 1 to about 3: 1. In some embodiments, the one or more organic acids comprise tartaric acid and methanesulfonic acid.
  • an amorphous solid dispersion described herein comprises an API, one or more acids, and a hydrophilic high-molecular weight material.
  • one or more acids comprise a first acid, which is a stronger acid, and a second acid, which is a weaker acid.
  • one or more acids comprises a first acid with a pKa of at most 2 and a second acid with a pKa of greater than 2.
  • the molar ratio of the first acid to API is about 1: 20 to about 20: 1.
  • the molar ratio of the first acid to API is about 1: 10 to about 10: 1.
  • the molar ratio of the first acid to API is about 1: 5 to about 5: 1. In some embodiments, the molar ratio of the first acid to API is about 1: 3 to about 3: 1. In some embodiments, the molar ratio of the first acid to API is about 1: 2 to about 2: 1. In some embodiments, the molar ratio of the first acid to API is about 1: 1.5 to about 1.5: 1. In some embodiments, the molar ratio of the first acid to API is about 1.
  • the molar ratio of the first acid to API is about 0.1: 1 to about 10: 1, about 0.5: 1 to about 5: 1, about 0.5: 1 to about 3: 1, about 0.5: 1 to about 1: 1, about 0.5: 1 to about 1.5: 1, about 0.5: 1 to about 2: 1, about 0.5: 1 to about 2.5: 1, about 0.5: 1 to about 3: 1, about 1: 1 to about 1.5: 1, about 1: 1 to about 2: 1, about 1: 1 to about 2.5: 1, about 1: 1 to about 3: 1, about 1.5: 1 to about 2: 1, about 1.5: 1 to about 2.5: 1, about 1.5: 1 to about 3: 1, about 2: 1 to about 2.5: 1, about 2: 1 to about 3: 1, or about 2.5: 1 to about 3: 1.
  • the weight ratio of the second acid to API is about 0.1: 1 to about 10: 1. In some embodiments, the weight ratio of the second acid to API is about 0.2: 1 to about 5: 1. In some embodiments, the weight ratio of the second acid to API is about 0.1: 1 to about 10: 1, about 1: 1 to about 8: 1, about 2: 1 to about 7: 1, about 4: 1 to about 7: 1, about 0.5: 1 to about 3: 1, about 0.5: 1 to about 1: 1, about 0.5: 1 to about 1.5: 1, about 0.5: 1 to about 2: 1, about 0.5: 1 to about 2.5: 1, about 0.5: 1 to about 3: 1, about 1: 1 to about 1.5: 1, about 1: 1 to about 2: 1, about 1: 1 to about 2.5: 1, about 1: 1 to about 3: 1, about 1.5: 1 to about 2: 1, about 1.5: 1 to about 2.5: 1, about 1.5: 1 to about 3: 1, about 2: 1 to about 2.5: 1, about 1.5: 1 to about 3: 1, about 2: 1 to about 2.5: 1, about 1.5: 1 to about 3
  • the mass ratio of the second acid to API is about 0.1: 1 to about 10: 1, about 0.2: 1 to about 5: 1, about 0.5: 1 to about 3: 1, about 0.2: 1 to about 1.2: 1, about 0.4: 1 to about 1: 1, about 0.5: 1 to about 1: 1, about 0.5: 1 to about 1.5: 1, about 0.5: 1 to about 2: 1, about 0.5: 1 to about 2.5: 1, about 0.5: 1 to about 3: 1, about 1: 1 to about 1.5: 1, about 1: 1 to about 2: 1, about 1: 1 to about 2.5: 1, about 1: 1 to about 3: 1, about 1.5: 1 to about 2: 1, about 1.5: 1 to about 2.5: 1, about 1.5: 1 to about 3: 1, about 2: 1 to about 2.5: 1, about 2: 1 to about 3: 1, or about 2.5: 1 to about 3: 1.
  • the weight ratio of the second acid to API is about 1: 20 to about 20: 1. In some embodiments, the weight ratio of the second acid to API is about 1: 10 to about 10: 1. In some embodiments, the weight ratio of the second acid to API is about 1: 5 to about 5: 1. In some embodiments, the weight ratio of the second acid to API is about 1: 3 to about 3: 1. In some embodiments, the weight ratio of the second acid to API is about 1: 2 to about 2: 1.
  • an amorphous solid dispersion and/or a pharmaceutical composition disclosed herein comprises one or more inorganic acids.
  • the one or more inorganic acids comprise one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, and phosphoric acid.
  • the one or more inorganic acids comprise hydrochloric acid.
  • the inorganic acid is completely ionized.
  • the inorganic acid is partially ionized.
  • partial ionization refers to an equilibrium in which 1%or more of the inorganic acid is ionized.
  • the one or more inorganic acids are present in the amorphous solid dispersion and/or in the pharmaceutical composition in an amount of from about 0.1%to about 99%by weight of the total composition. In some embodiments, the one or more inorganic acids are present in the amorphous solid dispersion and/or in the pharmaceutical composition in an amount of from about 0.1%to about 80%, 1%to about 80%, from about 1%to about 60%, from about 1%to about 50%, from about 10%to about 80%, from about 10%to about 60%, from about 10%to about 50%, from about 20%to about 80%, from about 20%to about 60%, from about 20%to about 50%, from about 30%to about 80%, from about 30%to about 60%, from about 30%to about 50%, or from about 30%to about 40%by weight of the total composition.
  • the one or more inorganic acids are present in the amorphous solid dispersion and/or in the pharmaceutical composition in an amount of about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45%by weight of the total composition.
  • the one or more inorganic acids comprise hydrochloric acid.
  • the one or more inorganic acids are present in the amorphous solid dispersion and/or in the pharmaceutical composition in an amount of about 1.0 mg to about 1000 mg, including but not limited to about 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg
  • the one or more inorganic acids are present in an amount of from about 0.1 mg to about 100 mg, from about 1 mg to about 50 mg, from about 2 mg to about 20 mg, from about 5 mg to about 15 mg, from about 7 mg to about 25 mg, from about 7 mg to about 20 mg, or from about 10 mg to about 18 mg.
  • an amorphous solid dispersion disclosed herein comprises a first acid and a second acid.
  • a molar ratio of the second acid to the first acid is from about 0.05: 1 to about 20: 1.
  • the molar ratio of the second acid to the first acid is from about 0.5: 1 to about 10: 1.
  • the molar ratio of the second acid to the first acid is from about 1: 1 to about 4: 1.
  • the molar ratio of the second acid to the first acid is about 2: 1.
  • a molar ratio of the API to the first acid is about 0.1: 1 to about 10: 1.
  • a molar ratio of the API to the first acid is from about 0.2: 1 to about 5: 1 or from about 0.5: 1 to about 2: 1. In some embodiments, a molar ratio of the API to the first acid is about 1: 1. In some embodiments, a mass ratio of the API to the second acid is about 0.05: 1 to about 20: 1. In some embodiments, a mass ratio of the API to the second acid is from about 0.1: 1 to about 5: 1 or from about 0.2: 1 to about 1: 1. In some embodiments, a mass ratio of the API to the second acid is about 0.5: 1.
  • the first acid has a pKa smaller than 1. In some embodiments, the first acid has a pKa that is at most 2. In some embodiments, the first acid is an organic acid. In some embodiments, the first acid is an inorganic acid. In some embodiments, the second acid is an organic acid. In some embodiments, the second acid is an inorganic acid. In some embodiments, both the first and the second acids are organic acids. In some embodiments, the first acid is methanesulfonic acid. In some embodiments, the second acid is tartaric acid. In some embodiments, the first acid is present in the amorphous solid dispersion and/or in the pharmaceutical composition in an amount of 5 mg to 200 mg.
  • the first acid is present in an amount of from about 10 mg to about 100 mg, from about 15 mg to about 50 mg, from about 20 mg to about 40 mg, from about 20 mg to about 30 mg, or from about 25 mg to about 30 mg.
  • the second acid is present in the amorphous solid dispersion and/or in the pharmaceutical composition in an amount of 5 mg to 400 mg.
  • the second acid is present in an amount of from about 10 mg to about 400 mg, from about 20 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 150 mg, from about 50 mg to about 100 mg, from about 30 mg to about 60 mg, from about 25 mg to about 75 mg, or from about 100 mg to about 200 mg.
  • an amorphous solid dispersion and/or a pharmaceutical composition described herein comprises a hydrophilic high-molecular weight material.
  • the hydrophilic high-molecular weight material comprises at least one of polyvinylpyrrolidone (povidone) (e.g., PVP-K30) , vinylpyrrolidone-vinyl acetate copolymer (copovidone or PVP-VA64, e.g., sold under the trade name VA 64) , polyvinyl alcohol (PVA) , polysaccharide, hydroxypropyl methylcellulose (HPMC or Hypromellose; e.g., HPMC-E5) , hydroxyethyl cellulose (HEC) , hydroxypropyl cellulose (HPC) , polyethylene oxide, hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) , sulfobutylether- ⁇ -cyclodextrin, hydroxy
  • the hydrophilic high-molecular weight material is PVP, copovidone, crospovidone, HPMC, or a combination thereof. In some embodiments, the hydrophilic high-molecular weight material comprises HPMC and crospovidone. In some embodiments, the hydrophilic high-molecular weight material comprises HPMC and PVP. In some embodiments, the hydrophilic high-molecular weight material comprises HPMC and copovidone. In some embodiments, the hydrophilic high-molecular weight material comprises copovidone and crospovidone.
  • an amorphous solid dispersion described herein comprises a hydrophilic high-molecular weight material.
  • the hydrophilic high-molecular weight material comprises at least one of polyvinylpyrrolidone (povidone) (e.g., PVP-K30) , vinylpyrrolidone-vinyl acetate copolymer (copovidone or PVP-VA64) , Soluplus, polyvinyl alcohol (PVA) , polysaccharide, hydroxypropyl methylcellulose (HPMC or Hypromellose; e.g., HPMC-E5) , hydroxyethyl cellulose (HEC) , hydroxypropyl cellulose (HPC) , polyethylene oxide, hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) , sulfobutylether- ⁇ -cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMC-AS-
  • the amorphous solid dispersion comprises PVP, HPMC, crospovidone, crospovidone, or a combination thereof. In some embodiments, the amorphous solid dispersion comprises HPMC. In some embodiments, the amorphous solid dispersion comprises PVP. In some embodiments, the amorphous solid dispersion comprises crospovidone. In some embodiments, the amorphous solid dispersion comprises crospovidone.
  • the hydrophilic high-molecular weight material is present in a disclosed amorphous solid dispersion and/or a disclosed pharmaceutical composition in an amount of at least 10 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 110 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 140 mg, at least 150 mg, at least 160 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 190 mg, or at least 200 mg.
  • the hydrophilic high-molecular weight material is present in a disclosed amorphous solid dispersion and/or a disclosed pharmaceutical composition in an amount of at most 30 mg, at most 40 mg, at most 50 mg, at most 60 mg, at most 70 mg, at most 75 mg, at most 80 mg, at most 90 mg, at most 100 mg, at least
  • the hydrophilic high-molecular weight material is present in an amount of from about 50 mg to about 150 mg, from about 55 mg to about 150 mg, from about 60 mg to about 150 mg, from about 65 mg to about 150 mg, from about 70 mg to about 150 mg, from about 75 mg to about 150 mg, from about 80 mg to about 150 mg, from about 85 mg to about 150 mg, from about 90 mg to about 150 mg, from about 95 mg to about 150 mg, from about 100 mg to about 150 mg, from about 105 mg to about 150 mg, from about 110 mg to about 150 mg, from about 115 mg to about 150 mg, from about 120 mg to about 150 mg, from about 125 mg to about 150 mg, from about 130 mg to about 150 mg, from about 135 mg to about 150 mg, from about 140 mg to about 150 mg, from about 145 mg to about 150 mg, from about 50 mg to about 145 mg, from about 50 mg to about 140 mg, from about 50 mg to about 130 mg, from about 50 mg to about 135 mg, from about 50 mg to about 125 mg,
  • the hydrophilic high-molecular weight material is present in an amount of 20 mg to 500 mg, 20 mg to 400 mg, 20 mg to 300 mg, 25 mg to 250 mg, 30 mg to 200 mg, 50 mg to 200 mg, 50 mg to 150 mg, 50 mg to 125 mg, 75 mg to 200 mg, 75 mg to 150 mg, 100 mg to 125 mg, or 100 mg to 150 mg.
  • the hydrophilic high-molecular weight material comprises PVP, HPMC, copovidone, crospovidone, or a combination thereof.
  • the amorphous solid dispersion comprises about 100 mg of HPMC.
  • a composition that comprises a hydrophilic high-molecular weight material (such as HPMC, PVP, copovidone, or a mixture thereof) that is present at an amount from about 1.0 mg to about 1000 mg, including but not limited to about 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29
  • the hydrophilic high-molecular weight material is present in the disclosed amorphous solid dispersion in an amount of 5%to 80%of a total weigh of the amorphous solid dispersion. In some embodiments, the hydrophilic high-molecular weight material is present in an amount of from about 10%to about 60%, from about 30%to about 50%, from about 5%to about 60%, from about 20%to about 50%, from about 20%to about 40%, from about 25%to about 35%, from about 28%to about 32%, from about 25%to about 30%, or from about 20%to about 30%of a total weigh of the amorphous solid dispersion.
  • the hydrophilic high-molecular weight material comprises from about 20%to about 50%of the total weight of the amorphous solid dispersion. In some embodiments, the hydrophilic high-molecular weight material comprises from about 20%to about 40%of the total weight of the amorphous solid dispersion.
  • the hydrophilic high-molecular weight material is present in an amount of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40%of a total weigh of the amorphous solid dispersion. In some embodiments, the hydrophilic high-molecular weight material is present in an amount of about 28%of a total weigh of the amorphous solid dispersion.
  • the hydrophilic high-molecular weight material is present in the disclosed pharmaceutical composition in an amount of 5%to 80%of a total weigh of the pharmaceutical composition. In some embodiments, the hydrophilic high-molecular weight material is present in an amount of from about 10%to about 60%, from about 30%to about 50%, from about 5%to about 60%, from about 20%to about 50%, from about 20%to about 40%, from about 25%to about 35%, from about 28%to about 32%, from about 25%to about 30%, or from about 20%to about 30%of a total weigh of the pharmaceutical composition. In some embodiments, the hydrophilic high-molecular weight material comprises from about 20%to about 50%of the total weight of the pharmaceutical composition.
  • the hydrophilic high-molecular weight material comprises from about 20%to about 40%of the total weight of the pharmaceutical composition. In some embodiments, the hydrophilic high-molecular weight material is present in an amount of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40%of a total weigh of the pharmaceutical composition.
  • a hydrophilic high-molecular weight material is present in the disclosed pharmaceutical composition as an excipient. In some embodiments, a hydrophilic high-molecular weight material is present in the disclosed pharmaceutical composition as an excipient of the amorphous solid dispersion in an amount of about 0.1%to about 20%by weight, including about 0.1%to about 10%, about 3%to about 8%, about 1%, about 2%, about 3%, about 5%, about 6%, about 7%, about 8%, about 9%or about 10%by weight of the pharmaceutical composition. In some embodiments, a hydrophilic high-molecular weight material is present in the disclosed pharmaceutical composition as an excipient of the amorphous solid dispersion in an amount of about 5%by weight of the pharmaceutical composition.
  • the hydrophilic high-molecular weight material can have a low, medium, or high viscosity.
  • the viscosity of the hydrophilic high-molecular weight material is about 4.0 -6.0 cP when measured at 2%in water at 20°C.
  • the viscosity of the hydrophilic high-molecular weight material is about 4.0 -6.0 cP when measured at 2%in water at 20°C.
  • the viscosity of the hydrophilic high-molecular weight material is less than about 120 cP when measured at 2%in water at 20°C.
  • the viscosity of the hydrophilic high-molecular weight material is from about 100 cP to about 20,000 cP when measured at 2%in water at 20°C. In some embodiments, the viscosity of the hydrophilic high-molecular weight material is less than about 4000 cP when measured at 2%in water at 20°C. In some embodiments, the viscosity of the hydrophilic high-molecular weight material is from about 4000 cP to about 100,000 cP when measured at 2%in water at 20°C.
  • the hydrophilic high-molecular weight material can have a particle size distribution.
  • a median diameter of the hydrophilic high-molecular weight material is less than 500 ⁇ m, less than 250 ⁇ m, less than 150 ⁇ m, less than 125 ⁇ m, less than 100 ⁇ m, less than 75 ⁇ m, less than 50 ⁇ m, less than 40 ⁇ m, less than 30 ⁇ m, less than 20 ⁇ m, or less than 10 ⁇ m.
  • a median diameter of the hydrophilic high-molecular weight material is at least 100 nm, at least 500 nm, at least 1 ⁇ m, at least 5 ⁇ m, at least 10 ⁇ m, at least 20 ⁇ m, at least 25 ⁇ m, at least 50 ⁇ m, at least 75 ⁇ m, at least 100 ⁇ m, at least 125 ⁇ m, or at least 150 ⁇ m.
  • a median diameter of the hydrophilic high-molecular weight material is from about 50 nm to about 1000 ⁇ m, from about 100 nm to about 500 ⁇ m, from about 1 ⁇ m to about 250 ⁇ m, from about 1 ⁇ m to about 200 ⁇ m, from about 1 ⁇ m to about 150 ⁇ m, or from about 50 ⁇ m to about 150 ⁇ m.
  • the present disclosure relates to pharmaceutical compositions and methods of administering thereof, the pharmaceutical compositions comprising an amorphous solid dispersion comprising an API.
  • the pharmaceutical compositions comprise one or more excipients or additives.
  • the pharmaceutical compositions comprise an API, one or more acids, and a first acid, wherein the first acid is organic; a second acid; and a high-molecular weight material.
  • the API is at least partially protonated.
  • the API is in a salt or solvate form.
  • the one or more acids comprise two organic acids.
  • Excipients and additives that can be used in a described pharmaceutical composition include additives well known in the art.
  • additives include, but are not limited to, anti-adherents (anti-sticking agents, glidants, flow promoters, lubricants) (e.g., talc, magnesium stearate, fumed silica (Carbosil, Aerosil) , micronized silica (Syloid No. FP 244, Grace U. S. A.
  • polyethylene glycols polyethylene glycols
  • surfactants waxes, stearic acid, stearic acid salts, stearic acid derivatives, starch, hydrogenated vegetable oils, sodium benzoate, sodium acetate, leucine, PEG-4000 and magnesium lauryl sulfate) anticoagulants (e.g., acetylated monoglycerides) , antifoaming agents (e.g., long-chain alcohols and silicone derivatives) , antioxidants (e.g., BHT, BHA, gallic acid, propyl gallate, ascorbic acid, ascorbyl palmitate, 4-hydroxymethyl-2, 6-di-tert-butyl phenol, tocopherol, etc.
  • binders i.e., agents that impart cohesive properties to powdered materials through particle-particle bonding, (e.g., matrix binders (dry starch, dry sugars) , film binders (PVP, starch paste, celluloses, bentonite, sucrose) ) , chemical binders (e.g., polymeric cellulose derivatives, such as carboxy methyl cellulose, crospovidone (i.e., cross linked polyvinyl N-pyrrolidone) , HPC, hydroxypropyl methylcellulose (HPMC) , etc., sugar syrups, corn syrup, water soluble polysaccharides (e.g., acacia, tragacanth, guar, alginates, etc) , gelatin, gelatin hydrolysate, agar, sucrose, dextrose, non-cellulosic binders (e.g., PVP, PEG, vinyl pyrroli
  • chelating agents e.g., EDTA and EDTA salts
  • coagulants e.g., alginates
  • opaquants e.g., titanium dioxide, food dyes, lakes, natural vegetable colorants, iron oxides, silicates, sulfates, magnesium hydroxide and aluminum hydroxide
  • coolants e.g.
  • cryoprotectants e.g., trehelose, phosphates, gelatin, dextran, mannitol, etc.
  • diluents or fillers e.g., lactose, mannitol, talc, magnesium stearate, sodium chloride, potassium chloride, citric acid, spray-dried lactose, hydrolyzed starches, directly compressible starch, microcrystalline cellulose (MCC) , cellulosics, sorbitol, sucrose, sucrose-based materials, calcium sulfate, dibasic calcium phosphate and dextrose disintegrants or super disintegrants (e.g., croscarmellose sodium, starch, starch derivatives, clays, gums, cellulose, cellulose derivatives, alginates, crosslinked polyvinylpyrrolidone, sodium starch glycolate and microcrystalline cellulose) , hydrogen bonding agents (e.g., magnesium oxide) , flavorants or desensitizers, (e.g., spray-dried flavors, essential oils and ethyl vanillin) , ion-exchange
  • Additives can also comprise materials such as proteins (e.g., collagen, gelatin, Zein, gluten, mussel protein, lipoprotein) , carbohydrates (e.g., alginates, carrageenan, cellulose derivatives, pectin, starch, chitosan) , gums (e.g., xanthan gum, gum arabic) , spermaceti, natural or synthetic waxes, carnuaba wax, fatty acids (e.g., stearic acid, hydroxystearic acid) , fatty alcohols, sugars, shellacs, such as those based on sugars (e.g., lactose, sucrose, dextrose) or starches, polysaccharide-based polymers (e.g., maltodextrin and maltodextrin derivatives, dextrates, cyclodextrin and cyclodextrin derivatives) , cellulosic-based polymers (e.g., micro
  • the pharmaceutical compositions comprise one or more preservatives.
  • Preservatives can include anti-microbials, antioxidants, and agents that enhance sterility.
  • Exemplary preservatives include ascorbic acid, ascorbyl palmitate, butylatedhydroxyanisole (BHA) , Butylatedhydroxytoulene (BHT) , propyl gallate, citric acid, EDTA and its salts, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (such as methylparaben, ethylparaben, propylparaben, butylparaben and their salts) , benzoic acid, sodium benzoate, potassium sorbate, vanillin, and the like.
  • an amorphous solid dispersion composition or a pharmaceutical composition described herein comprises an antioxidant.
  • the antioxidant comprises a-tocopherol acetate, acetone sodium bisulfite, acetylcysteine, ascorbic acid, vitamin E, ascorbyl palmitate, BHA, BHT, cysteine, cysteine hydrochloride, d-a-tocopherol (natural or synthetic) , dithiothreitol, monothioglycerol, nordihydroguaiaretic acid, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thiourea, or tocopherols.
  • an antioxidant or mixture of antioxidants are included as part of a solid dispersion.
  • Exemplary antioxidants include but are not limited to BHT, BHA, gallic acid, propyl gallate, ascorbic acid, ascorbyl palmitate, 4hydroxymethyl-2, 6-di-tert-butyl phenol, and tocopherol.
  • a pharmaceutical composition is provided that comprises from about 0.001%to about 10%by weight of the preservative (e.g., antioxidant) .
  • the percent weight of the preservative or antioxidant is from about 0.001 %to about 0.01 %, about 0.001 %to about 0.1 %, about 0.001 %to about 1 %, about 0.001 %to about 5 %, about 0.001 %to about 10 %, about 0.01 %to about 1 %, about 0.01 %to about 5 %, about 0.01 %to about 10 %, about 0.1 %to about 1 %, about 0.1 %to about 2 %, about 0.1 %to about 3 %, about 0.1 %to about 4 %, about 0.1 %to about 5 %, about 0.1 %to about 6 %, about 0.1 %to about 7 %, about 0.1 %to about 8 %, about 0.1 %to about 10 %, about 1 %to about 2 %, about 1 %to about 5 %, about 1 %to about 6 %, about 1 %to about 7 %, about 1 %to about 8
  • the excipients or additives comprise a filler, a binder, a disintegrating agent, a lubricant, an adsorbent, an acid, or a combination thereof.
  • the filler and/or binder comprises microcrystalline cellulose, crospovidone, lactose, or a combination thereof.
  • the disintegrating agent comprises microcrystalline cellulose.
  • the lubricant comprises magnesium stearate (abbreviated MgSt) .
  • the acid comprises an organic acid such as tartaric acid.
  • the adsorbent is silica.
  • the pharmaceutical composition comprises microcrystalline cellulose, lactose, crospovidone, magnesium stearate, silicon dioxide, an organic acid, or a combination thereof.
  • the weight ratio of the excipients to the API is from about 0.1: 1 to about 10: 1. In some embodiments, the weight ratio of the excipients to the API is from about 0.5: 1 to about 5: 1, from about 0.5: 1 to about 4: 1, from about 0.5: 1 to about 3: 1, from about 0.6: 1 to about 4: 1, from about 0.7: 1 to about 3: 1, from about 0.8: 1 to about 2: 1, from about 0.9: 1 to about 1.1: 1, from about 1: 1 to about 3: 1, from about 1: 1 to about 4: 1, from about 1: 1 to about 5: 1, or from about 1: 1 to about 6: 1.
  • amorphous solid dispersions described herein comprise an API, a surfactant, a non-ionic hydrophilic polymer, and optionally an adsorbent.
  • the surfactant is selected from polymeric non-ionic surfactants and phospholipids.
  • the polymeric non-ionic surfactant comprises a block copolymer of polyethylene glycol and polypropylene glycol.
  • the polymeric non-ionic surfactant is Poloxamer 188.
  • the surfactant comprises one or more phospholipids.
  • the surfactant comprises one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, plasmalogen, sphingomyelin, and phosphatidic acid. In some embodiments, the surfactant comprises lecithin.
  • amorphous solid dispersions described herein comprise a non-ionic hydrophilic polymer.
  • the non-ionic hydrophilic polymer comprises oligosaccharide, polysaccharide, vinylpyrrolidone-vinyl acetate copolymer (copovidone) , polyvinylpyrrolidone (PVP or povidone) , polyvinyl alcohol (PVA) , polysaccharide, hydroxypropyl methylcellulose (HPMC or hypromellose) , hydroxyethyl cellulose (HEC) , hydroxypropyl cellulose (HPC) , polyethylene oxide, hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) , sulfobutylether- ⁇ -cyclodextrin, hydroxypropylmethylcellulose acetate succinate (HPMCAS) , polyethylene glycol (PEG) , polyvinyl caprolactam–polyvinyvinyl
  • the non-ionic hydrophilic polymer comprises HPMC, copovidone, PVP, HP- ⁇ -CD, PVA, HPMCAS, PVAc-PVCap-PEG, or a combination thereof. In some embodiments, the non-ionic hydrophilic polymer comprises about 5%to about 70%of the total weight of the amorphous solid dispersion. In some embodiments, the non-ionic hydrophilic polymer comprises from about 5%to about 60%, from about 5%to about 50%, from about 10%to about 50%, from about 10%to about 40%, from about 20%to about 40%, or from about 20%to about 30%of the total weight of the amorphous solid dispersion.
  • Amorphous solid dispersions described herein can comprise an adsorbent.
  • a disclosed amorphous solid dispersion comprises an API, one or more acids, an adsorbent and a hydrophilic high-molecular weight material.
  • the excipients or additives of described pharmaceutical compositions comprise an adsorbent.
  • Adsorbents can be solid, porous or super porous adsorption materials. They can comprise numerous micro-or nano-pores within their structures, resulting in very large surface areas, for example, greater than 500 m 2 /g.
  • Exemplary adsorbents include, without limitation, silicon dioxide, active carbon, magnesium aluminum silicate, diatomite, microcrystalline cellulose (MCC) , silicified microcrystalline cellulose (SMCC) , talc, crosslinked povidone, sodium carboxymethylcellulose, sodium carboxymethyl starch, and also sugars or sugar alcohols such as sorbitol, mannitol, lactose, cyclodextrin, and maltodextrin.
  • the adsorbent is silicon dioxide.
  • an adsorbent such as silicon dioxide is present in a pharmaceutical composition described herein in an amount of at least 5 mg, at least 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, or 200 mg.
  • the adsorbent is present in an amount of about 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 225 mg, or 250 mg.
  • the adsorbent is present in an amount of no more than 300 mg, 250 mg, 225 mg, 200 mg, 175 mg, 150 mg, 125 mg, 100 mg, 90 mg, 80 mg, 75 mg, 60 mg, 55 mg, 50 mg, or 25 mg.
  • the adsorbent is present in an amount of from about 0.1 mg to about 500 mg. In some embodiments, the adsorbent is present in an amount of from about 0.1 mg, about 0.2 mg, about 0.5 mg, about 1 mg, or 2 about 1 mg to about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, or about 200 mg. In some embodiments, the adsorbent is present in an amount of from about 1 mg to about 50 mg, from about 1 mg to about 20 mg, from about 1 mg to about 10 mg, or from about 1 mg to about 5 mg.
  • the amorphous solid dispersion is granulated and incorporated into a pharmaceutical composition with extra granular additives.
  • the silicon dioxide is present outside of the amorphous solid dispersion as an extra-granular additive.
  • silicon dioxide is present in the amorphous solid dispersion as well as being an extra-granular additive.
  • an adsorbent such as silicon dioxide is present in the disclosed amorphous solid dispersion.
  • the adsorbent comprises from about 1%to about 50%of the total weight of the amorphous solid dispersion.
  • the adsorbent comprises from about 1%to about 40%, from about 1%to about 30%, from about 1%to about 25%, from about 1%to about 20%, from about 1%to about 15%, from about 1%to about 10%, from about 5%to about 40%, from about 5%to about 25%, from about 5%to about 20%, from about 5%to about 15%, or from about 5%to about 10%of the total weight of the amorphous solid dispersion.
  • an adsorbent described herein has a median diameter of 1-1000 nm. In some embodiments, an adsorbent described herein has a median diameter of from about 1 nm to about 750 nm, from about 1 nm to about 500 nm, from about 1 nm to about 250 nm, from about 1 nm to about 150 nm, from about 1 nm to about 100 nm, from about 1 nm to about 50 nm, from about 1 nm to about 25 nm, from about 10 nm to about 500 nm, from about 10 nm to about 250 nm, from about 10 nm to about 150 nm, from about 10 nm to about 100 nm, from about 10 nm to about 50 nm, from about 10 nm to about 25 nm, from about 50 nm to about 500 nm, from about 50 nm to about 250 nm, from about 50 nm to about 150 nm,
  • an adsorbent described herein has a median diameter of from about 100 nm to about 1000 nm, from about 100 nm to about 750 nm, from about 200 nm to about 1000 nm, from about 200 nm to about 750 nm, from about 500 nm to about 1000 nm, or from about 500 nm to about 750 nm. In some embodiments, an adsorbent described herein has a median diameter larger than 1000 nm.
  • compositions described herein comprise an API (such as palbociclib or neratinib, or a salt or solvate thereof) , a hydrophilic polymer, and a surfactant.
  • the API, hydrophilic polymer, and the surfactant are formulated as an amorphous solid dispersion.
  • the surfactant is selected from polymeric non-ionic surfactants and phospholipids.
  • the surfactants are compounds or mixture of compounds comprising a hydrophobic group (usually a hydrocarbon chain) and a hydrophilic group. They may perform one or more roles including solubility enhancer, bioavailability enhancer, stability enhancer, antioxidant and emulsifying agent.
  • surfactants include, but are not limited to, phospholipids, sucrose esters of fatty acids, polyoxyl stearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polysorbate, glyceryl monostearate, sodium lauryl sulfate, sodium dodecyl sulfate, lauromacrogol Arlasolve, Poloxamers, Labrafil, Labrasol, Tween 80, Tocopheryl polyethylene glycol 1000 succinate (simply TPGS or Vitamin E TPGS) and the like.
  • the surfactant used in the present disclosure can be a non-ionic surfactant.
  • a non-ionic surfactant has no charged groups in its head.
  • Exemplary nonionic surfactants include, without limitation, fatty alcohols, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and oleyl alcohol.
  • nonionic surfactants include, but are not limited to, polyethylene glycol alkyl ethers (such as octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether) , polypropylene glycol alkyl ethers, glucoside alkyl ethers (such as decyl glucoside, lauryl glucoside, octyl glucoside) , polyethylene glycol octylphenyl ethers (such as Triton X-100) , polyethylene glycol alkylphenyl ethers (such as nonoxynol-9) , glycerol alkyl esters (such as glyceryl laurate) , polyoxyethylene glycol sorbitan alkyl esters (such as polysorbate) , sorbitan alkyl esters (such as Spans) , cocamide MEA, cocamide DEA, dodecamide
  • the surfactant comprises two more repeating units, such as polyoxyalkylene units.
  • the surfactant is a non-ionic surfactant that comprises polyethylene glycol.
  • the surfactant is a block copolymer of polyethylene glycol and polypropylene glycol.
  • the surfactant is a poloxamer such as poloxamer 188.
  • the non-ionic surfactant has a number average molecular weight of from about 1000 to about 100,000 Da , 2000 to about 20,000 Da, from about 4000 to about 15,000 Da, from about 6000 to about 12,000 Da, or from about 7000 to about 10,000 Da. In some embodiments, the non-ionic surfactant has a number average molecular weight of from about 7000 to about 10,000 Da.
  • the non-ionic surfactant has an ethylene glycol content of from about 30wt%to about 99 wt%, from about 50 wt%to about 95 wt%, from about 60 wt%to about 95wt%, from about 75 wt%to about 90 wt%, or from about 80 wt%to about 85 wt%. In some embodiments, the non-ionic surfactant has an ethylene glycol content of from about 80 wt%to about 85 wt%.
  • the surfactants are selected from fatty acids, phospholipids, sphingolipids, saccharolipids, polyketides, sterol lipids, prenol lipids and the like.
  • phospholipids are made up of glycerol to which is attached a phosphate group and two fatty acids.
  • Other terms in the art for phospholipids include glycerophospholipids, phosphoglycerides, diacylglycerides and the like.
  • Phospholipids may be further modified by substitution onto one or more for the hydrocarbon chains.
  • phospholipids are selected from glycerophospholipid, sphingolipid, and/or phospholipid derivatives.
  • glycerophospholipids include, but are not limited to phosphatidylcholine, phosphatidyl ethanolamine, phosphatidyl ethanolamine, phosphatidyl serine, phosphatidyl glycerol, diphosphatidylglycerol, phosphatidylinositol, and mixtures thereof.
  • Phospholipid derivatives according to the present invention include, but are not limited to dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipentadeanoylphosphatidylcholine, dilauroylphosphatidylchoine, dipalmitoylphosphatidylcholine (DPPC) , distearoylphosphatidylcholine (DSPC) , diarachidonyiphosphatidylcholine (DAPC) , dioleoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine (DPPE) , and distearoylphosphatidylethanolamine (DSPE) , disteraoylphosphatidylglycerol (DSPG) , phosphatidylinositol, dipalmitoylphosphatidic acid (DPPA) , distearoylphosphatidic acid (DSPA) , and the like, and mixtures
  • the phospholipid is present in the pharmaceutical composition and/or in the amorphous solid dispersion in an amount of about 25 mg to about 200 mg. In some embodiments, the phospholipid is present in an amount of about 50 mg to 150 mg. In some embodiments, the phospholipids comprise 2.5%-20%of the total weight of the pharmaceutical composition. In some embodiments, the phospholipids comprise 5%-17%of the total weight of the pharmaceutical composition. In some embodiments, the phospholipids comprise greater than 80%phosphatidylcholine.
  • Phosphatidylcholines can refer to phospholipids wherein a choline group (Me 3 N + -CH 2 -CH 2 -O-) is attached to the phosphate group.
  • a non-limiting example of a phosphatidylcholine is 1-oleoyl-2-palmitoyl-phosphatidyl choline, as shown below:
  • the surfactant is a phospholipid. In some embodiments, the phospholipid is phosphatidylcholine. In some embodiments, the phospholipid is a mixture comprising phosphatidylcholine. In some embodiments, the surfactant is lecithin. In some embodiments, the lecithin is comprised of phosphatidylcholine. In some embodiments, the lecithin contains more than 25%of phosphatidylcholine. In some embodiments, the lecithin contains more than 80%of phosphatidylcholine. In some embodiments, the phosphatidylcholine is from egg origin. In some embodiments, the phosphatidylcholine is from or soybean origin.
  • the surfactant is lecithin.
  • the USP 40 definition of lecithin is “acomplex mixture of acetone-insoluble phosphatides, which consist chiefly of phophatidylcholine, phosphatidylethanolamine, phosphatilinositol, and phosphatidic acid, present in conjunction with various amounts of other substances such as triglycerides, fatty acids, and carbohydrates, as separated from the crude vegetable oil source. ”
  • lecithin is a mixture of phospholipids. Lecithin can be isolated from various sources including, but not limited to eggs, soybeans, milk, marine sources, rapeseed, cottonseed and sunflower.
  • the lecithin used in the disclosed amorphous solid dispersions and/or pharmaceutical compositions is isolated from egg yolk.
  • compositions described herein include an API, a hydrophilic polymer, and a surfactant.
  • pharmaceutical compositions described herein comprises an API, a hydrophilic polymer, and a phospholipid or poloxamer.
  • the API is palbociclib or a pharmaceutically acceptable salt thereof.
  • the API is palbociclib.
  • the API is a pharmaceutically acceptable salt of palbociclib.
  • the API is neratinib or a pharmaceutically acceptable salt thereof, such as neratinib maleate.
  • the API is neratinib.
  • the API is neratinib maleate.
  • the surfactant is present in an amorphous solid dispersion and/or in a pharmaceutical composition disclosed herein in an amount of no less than 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 225 mg, or 250 mg.
  • the surfactant is present in an amorphous solid dispersion and/or in a pharmaceutical composition disclosed herein in an amount of no more than 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 225 mg, 250 mg, 300 mg, or 500 mg.
  • the surfactant is present in an amorphous solid dispersion and/or in a pharmaceutical composition disclosed herein in an amount of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 225 mg, or 250 mg.
  • the surfactant is present in an amount of 50 mg to 500 mg.
  • the surfactant is present in an amount of 75 mg to 300 mg.
  • the surfactant is present in an amount of 100 mg to 200 mg.
  • the surfactant is present in an amount of 125 mg to 175 mg.
  • the surfactant comprises poloxamer or phospholipids such as lecithin.
  • the surfactant is a polymeric non-ionic surfactant such as poloxamer.
  • the surfactant comprises phospholipids such as lecithin.
  • the pharmaceutical composition described herein additionally comprise one or more adsorbents.
  • the pharmaceutical composition described herein additionally comprise one or more other additives.
  • other additives comprise organic and inorganic acids.
  • other additives comprise antioxidants.
  • the surfactant e.g., polymeric non-ionic surfactants or phospholipids
  • the surfactant is present in an amorphous solid dispersion and/or in a pharmaceutical composition disclosed herein in an amount from about 1.0 mg to about 1000 mg, including but not limited to about 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28
  • compositions and/or amorphous solid dispersions described herein comprise an API, a hydrophilic polymer, and a surfactant.
  • the surfactant e.g., polymeric non-ionic surfactants or phospholipids
  • the composition is an amorphous solid dispersion.
  • the composition is a pharmaceutical composition.
  • the surfactant comprises 1%-30%of the total weight of the composition.
  • the surfactant comprises 5%-20%of the total weight of the composition.
  • the surfactant comprises 10%-17%of the total weight of the composition.
  • the surfactant comprises about 15%, about 16%, about 17%, about 18%, about 19%or about 20%of the total weight of the composition.
  • the ratio by weight of the hydrophilic polymer to the surfactant is at least 0.75: 1, at least 1: 1, at least 1.1: 1, at least 1.2: 1, at least 1.3: 1, at least 1.4: 1, at least 1.5: 1, or at least 2: 1.
  • compositions provided herein can be in unit-dosage forms or multiple-dosage forms.
  • Unit-dosage forms refer to physically discrete units suitable for administration to human or non-human animal subjects and packaged individually. Each unit-dose can contain a predetermined quantity of an active ingredient (s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include, but are not limited to, individually packaged tablets and capsules. In some embodiments, the pharmaceutical compositions are administered as capsules.
  • compositions may also be formulated as a modified release dosage form, including immediate-, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, extended, accelerated-and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • These dosage forms can be prepared according to known methods and techniques (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. 126, which are herein incorporated by reference in their entirety) .
  • compositions comprising an amorphous solid dispersion that comprises an API.
  • the API is palbociclib or a salt or solvate thereof.
  • the API is palbociclib, wherein the palbociclib is at least partially protonated.
  • the API is neratinib or a salt or solvate thereof.
  • the API is neratinib, wherein the neratinib is at least partially protonated.
  • the API is one listed in Table A.
  • the amorphous solid dispersion comprises up to 99%, up to 90%, up to 85%, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, up to 55%, up to 50%, up to 45%, or up to 40%of the pharmaceutical composition by weight.
  • the amorphous solid dispersion comprises from 10%to 90%, 20%to 90%, 30%to 90%, 40%to 90%, 50%to 90%, 60%to 90%, 70%to 90%, 80%to 90%, 30%to 80%, 40%to 80%, 50%to 80%, 60%to 80%, 20%to 90%, 20%to 80%, 20%to 70%, 20%to 60%, or 20%to 50%of the pharmaceutical composition by weight.
  • the pharmaceutical composition comprises the amorphous solid dispersion in an amount of about 50%to about 95%of a total weight of the pharmaceutical composition; microcrystalline cellulose in an amount of about 1%to about 12%of a total weight of the pharmaceutical composition; magnesium stearate in an amount of about 0.2%to about 5%of a total weight of the pharmaceutical composition; silica in an amount of about 0.2%to about 5%of a total weight of the pharmaceutical composition; and an organic acid in an amount of about 5%to about 20%of a total weight of the pharmaceutical composition.
  • the pharmaceutical composition comprises an amorphous solid dispersion that comprises about 70%to about 80%of a total weight of the pharmaceutical composition; microcrystalline cellulose in an amount of about 5%to about 6%of a total weight of the pharmaceutical composition; crospovidone in an amount of about 4.5%to about 5.5%of a total weight of the pharmaceutical composition; magnesium stearate in an amount of about 0.5%to about 1.5%of a total weight of the pharmaceutical composition; silica in an amount of about 0.5%to about 1.5%of a total weight of the pharmaceutical composition; and an organic acid in an amount of about 11%to about 13%of a total weight of the pharmaceutical composition.
  • a pharmaceutical composition disclosed herein comprises an amorphous solid dispersion comprising palbociclib or a salt or solvate thereof, methanesulfonic acid, tartaric acid, and one or more excipients selected from HPMC; microcrystalline cellulose; crospovidone; magnesium stearate; silica; and an acid (such as tartaric acid) .
  • the palbociclib is at least partially protonated.
  • the salt of palbociclib is palbociclib mesylate.
  • the amorphous solid dispersion comprises about 60%to about 90%of a total weight of the pharmaceutical composition.
  • the amorphous solid dispersion comprises about 75.7%of a total weight of the pharmaceutical composition. In some embodiments, the palbociclib or a salt or solvate thereof is present in an amount of about 30%to about 40%of a total weight of the amorphous solid dispersion. In some embodiments, the palbociclib or a salt or solvate thereof is present in an amount of about 35.5%of a total weight of the amorphous solid dispersion. In some embodiments, the amorphous solid dispersion comprises a mesylate salt of palbociclib.
  • the amorphous solid dispersion comprises methanesulfonic acid in an amount of from about 5%to about 15%, from about 2%to about 10%, or from about 2%to about 15%of a total weight of the amorphous dispersion. In some embodiments, the amorphous solid dispersion comprises methanesulfonic acid in an amount of about 7.6%of a total weight of the amorphous dispersion. In some embodiments, the amorphous solid dispersion comprises tartaric acid in an amount of from about 20%to about 40%or from about 25%to about 30%of a total weight of the amorphous dispersion.
  • the amorphous solid dispersion comprises tartaric acid in an amount of about 28.4%of a total weight of the amorphous dispersion.
  • the amorphous solid dispersion comprises a hydrophilic high-molecular weight material in an amount of from about 20%to about 40%or from about 25%to about 30%of a total weight of the amorphous dispersion.
  • the amorphous solid dispersion comprises HPMC in an amount of about 28.4%of a total weight of the amorphous dispersion.
  • microcrystalline cellulose is present in an amount of about 1%to about 10%of a total weight of the pharmaceutical composition.
  • microcrystalline cellulose is present in an amount of about 5.5%of a total weight of the pharmaceutical composition.
  • crospovidone is present in an amount of about 1%to about 10%of a total weight of the pharmaceutical composition.
  • crospovidone is present in an amount of about 5%of a total weight of the pharmaceutical composition.
  • magnesium stearate is present in an amount of about 0.1%to about 5%of a total weight of the pharmaceutical composition.
  • magnesium stearate is present in an amount of about 1%of a total weight of the pharmaceutical composition.
  • silica is present in an amount of about 0.1%to about 5%of a total weight of the pharmaceutical composition. In some embodiments, silica is present in an amount of about 1%of a total weight of the pharmaceutical composition.
  • a pharmaceutical composition described herein comprises palbociclib, methanesulfonic acid, tartaric acid, HPMC, microcrystalline cellulose, crospovidone, magnesium stearate, silica, or a combination thereof.
  • the pharmaceutical composition comprises palbociclib in an amount equivalent to 75 mg, 100 mg, or 125 mg palbociclib free base.
  • the pharmaceutical composition described herein further comprises about 20 mg to 30 mg of methanesulfonic acid, about 125 mg to 175 mg of tartaric acid, about 75 mg to 100 mg of HPMC, about 20 mg to 30 mg of microcrystalline cellulose, about 20 mg to 30 mg of crospovidone, about 1 mg to 10 mg of magnesium stearate, and about 1 mg to 10 mg of silica.
  • the pharmaceutical composition described herein comprises about 26.7 mg of methanesulfonic acid, about 155 mg of tartaric acid, about 100 mg of HPMC, about 25.5 mg of microcrystalline cellulose, about 23.3 mg of crospovidone, about 4.7 mg of magnesium stearate, and about 4.7 mg of silica.
  • compositions described herein optionally comprise an inner matrix comprising an amorphous solid dispersion of the API, and an outer matrix comprising at least one pharmaceutically acceptable excipient.
  • the API is palbociclib.
  • the API is neratinib or a pharmaceutically acceptable salt thereof, such as neratinib maleate.
  • the API is one listed in Table A.
  • the inner matrix comprises an amorphous solid dispersion and at least one pharmaceutically acceptable excipient.
  • the inner matrix is formed by mixing the amorphous solid dispersion with one or more pharmaceutically acceptable excipients, compressing the mixture, milling the compressed mixture, and screening the milled compressed mixture to produce particulates that are less than about 1000, 900, 800, 700, 600, 550, 500, 450, 400, 350, 300, 200, or 100 microns in size.
  • an outer matrix is added by mixing at least one pharmaceutically acceptable excipient with the particulates of the inner matrix.
  • the outer matrix encapsulates the inner matrix particulates.
  • the outer matrix partially encapsulates the inner matrix particulates.
  • the outer matrix creates a thin boundary between the majority of the inner matrix particulates.
  • the concentration of the API is higher in the inner matrix as compared to the outer matrix.
  • the inner and outer matrix share at least one pharmaceutically acceptable excipient.
  • the concentration of the at least one shared pharmaceutically acceptable excipient in the inner and outer matrices is non equal.
  • less than 20%of the API in the composition is present in the outer matrix.
  • less than 10%of the API in the composition is present in the outer matrix.
  • less than 5%of the API in the composition is present in the outer matrix.
  • less than 1%of the API in the composition is present in the outer matrix.
  • the present pharmaceutical compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, suppositories, emulsions, suspensions, or any other form suitable for use.
  • Preferred pharmaceutical compositions are formulated for oral delivery.
  • the pharmaceutically acceptable vehicle is a capsule.
  • Capsules may be hard capsules or soft capsules, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol) .
  • the capsule contains about 1000 mg of the pharmaceutical composition. In some embodiments, the capsule contains less than 1000 mg of the pharmaceutical composition.
  • Capsules can be of any size. Examples of standard sizes include, but are not limited to those listed in Table B, (#000, #00, #0, #1, #2, #3, #4, and #5) . See, e.g., Remington's Pharmaceutical Sciences, page 1658-1659 (Alfonso Gennaro ed., Mack Publishing Company, Easton Pa., 18th ed., 1990) , which is incorporated by reference. In some embodiments, the capsules used herein are of size #00 or #0.
  • the amorphous solid dispersions described herein can increase the dissolution rate of the API, e.g., as shown in Figure 1.
  • about 80%or more of the API is dissolved in about 10 minutes or less.
  • about 70%or more of the API is dissolved in about 10 minutes or less.
  • about 60%or more of the API is dissolved in about 10 minutes or less.
  • about 50%or more of the API is dissolved in about 10 minutes or less.
  • about 80%or more of the API is dissolved in about 20 minutes or less.
  • about 70%or more of the API is dissolved in about 20 minutes or less.
  • about 60%or more of the API is dissolved in about 20 minutes or less.
  • about 50%or more of the API is dissolved in about 20 minutes or less. In some embodiments, about 80%or more of the API is dissolved in about 30 minutes or less. In some embodiments, about 70%or more of the API is dissolved in about 30 minutes or less. In some embodiments, about 60%or more of the API is dissolved in about 30 minutes or less. In some embodiments, about 50%or more of the API is dissolved in about 30 minutes or less. In some embodiments, about 80%or more of the API is dissolved in about 60 minutes or less. In some embodiments, about 70%or more of the API is dissolved in about 60 minutes or less. In some embodiments, about 60%or more of the API is dissolved in about 60 minutes or less. In some embodiments, about 50%or more of the API is dissolved in about 60 minutes or less.
  • compositions described herein can be administered for the treatment or prevention of diseases.
  • pharmaceutical compositions may be administered or applied singly, or in combination with other agents.
  • Pharmaceutical compositions may also be administered or applied singly, in combination with other pharmaceutically active agents.
  • Provided herein are methods of treatment and prophylaxis by administration to a subject in need of such treatment of a therapeutically effective amount of a pharmaceutical composition of the invention.
  • the subject may be an animal, e.g., a mammal such as a human.
  • pharmaceutical compositions described herein are administered orally.
  • the pharmaceutical compositions described herein can be administered in prescribed regimens.
  • the pharmaceutical compositions are administered 3 times per day, twice per day, once per day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every week, twice every month, or once every month.
  • the dosage of API is 50 mg and is administered once a day.
  • the dosage of API is 75 mg and is administered once a day.
  • the dosage of API is 100 mg and is administered once a day.
  • the dosage of API is 125 mg and is administered once a day.
  • the dosage of API is 150 mg and is administered once a day.
  • the dosage of API is 200 mg and is administered once a day. In some embodiments, the dosage of API is 240 mg and is administered once a day. In some embodiments, the pharmaceutical composition is administered to the subject in an amount equivalent to 75 mg of palbociclib free base daily. In some embodiments, the pharmaceutical composition is administered to the subject in an amount equivalent to 100 mg of palbociclib free base daily. In some embodiments, the pharmaceutical composition is administered to the subject in an amount equivalent to 125 mg of palbociclib free base daily. In some embodiments, the pharmaceutical composition is administered to the subject in an amount equivalent to 125 mg of palbociclib free base daily for 21 days as a starting dose followed by 7 days off treatment.
  • 240 mg of neratinib maleate is administered daily. In some embodiments, neratinib maleate is administered following tratuzumab based therapy. In some embodiments, neratinib maleate is administered daily for one year. In some embodiments, loperamide is administered with the first dose of neratinib maleate and dosing continues for more than 50 days. In some embodiments, 240 mg of neratinib maleate is administered daily for up to one year. In some embodiments, 240 mg of neratinib maleate is administered once daily for 21 days in combination with capecitabine on days 1-14. In some embodiments, the dosage of 240 mg is divided into six 40 mg tablets. In some embodiments, the dosage is less than 240 mg.
  • the pharmaceutical compositions described herein can be administered with or without food.
  • the pharmaceutical composition is administered to the subject orally with food.
  • the pharmaceutical composition is administered to the subject orally without food.
  • the pharmaceutical composition is administered to the subject orally with food for 21 days followed by 7 days off treatment.
  • the pharmaceutical composition is administered to the subject orally with or without food for 21 days followed by 7 days off treatment.
  • the pharmaceutical composition is administered to the subject for a period of 1 to 7 weeks and followed by an off treatment of 1 to 2 weeks.
  • the pharmaceutical composition is administered to the subject for a period of one day to one year.
  • the pharmaceutical composition is administered approximately the same time each day.
  • compositions described herein can be administered for a cycle of 1 to 56 weeks.
  • a cycle comprises 28 days including 21 consecutive days of administering the pharmaceutical composition and 7 days off treatment.
  • the method comprises administering 500 mg of fulvestrant on days 1, 15 and 29 and once monthly thereafter.
  • the dosages of the pharmaceutical composition is adjusted.
  • a starting dose of the pharmaceutical composition is equivalent to 125 mg of palbociclib free base daily.
  • a starting dose of the pharmaceutical composition is equivalent to 100 mg of palbociclib free base daily.
  • a starting dose of the pharmaceutical composition is equivalent to 50mg of palbociclib free base daily.
  • the method of treating a disease comprises dose interruption and/or dose reductions based on individual safety and tolerability.
  • a first dose reduction comprises administering the pharmaceutical composition in an amount equivalent to 100 mg of palbociclib free base daily.
  • a second dose reduction comprises administering the pharmaceutical composition in an amount equivalent to 75 mg of palbociclib free base daily.
  • a pharmaceutical composition described herein can be used for treating a disease or condition in a subject.
  • the subject is diagnosed with cancer.
  • the subject is an adult patient with cancer.
  • the pharmaceutical compositions is used to treat or prevent breast cancer, liver cancer, ovarian epithelial carcinoma, leukemia, non-small cell lung cancer, multiple myeloma, colorectal cancer, liposarcoma, melanoma, melanoma cell lymphoma, or solid tumors.
  • a pharmaceutical composition described herein is used to treat a solid cancer.
  • the cancer is hormone receptor (HR) -negative, progesterone receptor (PR) -positive, and/or human epidermal growth factor receptor 2 (HER2) -positive breast cancer.
  • the cancer is a breast cancer.
  • the cancer is a hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HER2) -negative advanced, or metastatic breast cancer.
  • the cancer is hormone receptor (HR) –positive, HER2-negative advanced or metastatic breast cancer.
  • the pharmaceutical composition is used in combination with an aromatase inhibitor, and wherein the aromatase inhibitor is an initial endocrine based therapy in postmenopausal women.
  • the aromatase inhibitor is anastrozole, exemestane, or letrozole.
  • the pharmaceutical composition is used in combination with fulvestrant, wherein the subject is a women with disease progression following endocrine therapy.
  • a composition described herein is used in combination with aromatase inhibitor as initial endocrine-based therapy.
  • the pharmaceutical composition is used in combination with capecitabine, for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting.
  • the pharmaceutical composition is used for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer, to follow adjuvant trastuzumab based therapy.
  • the subject is a female. In some embodiments, the subject is a male.
  • the pharmaceutical composition is used to treat a cancer selected from the group consisting of breast cancer
  • cancer is selected from the group consisting of acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancers, brain tumors, such as cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, bronchial adenomas, Burkitt lymphoma, carcinoma of unknown primary origin, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leuk
  • disclosed herein is a method of inhibiting CDK4/6 in a subject, comprising administering to a subject a pharmaceutical composition or an amorphous solid dispersion described herein. In one aspect, disclosed herein is a method of modulating CDK4/6 in a subject, comprising administering to a subject a pharmaceutical composition or an amorphous solid dispersion described herein. In some embodiments, the subject has cancer.
  • a pharmaceutical composition described herein is used in combination with a second therapeutic agent.
  • the second therapeutic agent is an aromatase inhibitor.
  • the aromatase inhibitor is anastrozole, exemestane, or letrozole.
  • a pharmaceutical composition described herein is used in combination with an aromatase inhibitor as an initial endocrine-based therapy in postmenopausal women.
  • the second therapeutic agent is an estrogen receptor degrader.
  • the second therapeutic agent is fulvestrant.
  • a pharmaceutical composition described herein is used in combination with fulvestrant.
  • Fulvestrant or 7 ⁇ - [9- [ (4, 4, 5, 5, 5-Pentafluoropentyl) -sulfinyl] nonyl] estra-1, 3, 5 (10) -triene-3, 17 ⁇ -diol, is a selective estrogen receptor degrader (SERD) .
  • Fulvestrant is sold under the brand name Faslodex, and alternative names of fulvestrant include ICI-182780, ZD-182780, and ZD-9238.
  • a pharmaceutical composition described herein can be used in combination with fulvestrant in patients with disease progression following endocrine therapy.
  • a pharmaceutical composition described herein is taken orally with food.
  • a pharmaceutical composition described herein is taken orally with food in combination with an aromatase inhibitor or fulvestrant.
  • the starting dose is 125 mg of palbociclib once daily taken with food for 21 days.
  • the starting dose is taken once daily with food for 21 days followed by 7 days off treatment.
  • the starting dose is taken for between 7 and 30 days, followed by at least 1 day of off treatment.
  • a method of manufacturing a pharmaceutical composition comprising an amorphous solid dispersion.
  • a method of manufacturing an amorphous solid dispersion comprises one or more steps selected from (i) combining a solvent, a hydrophilic high-molecular weight material, and an API or a salt or solvate thereof, thereby producing a combined mixture; and (ii) removing at least a portion of the solvent from the mixture, thereby producing an amorphous solid dispersion.
  • a method of manufacturing an amorphous solid dispersion comprises one or more steps selected from (i) combining a solvent, a hydrophilic high-molecular weight material, and an API or a salt or solvate thereof thereby producing a combined mixture; (ii) contacting the combined mixture with an adsorbent; and (iii) removing at least a portion of the solvent from the mixture, thereby producing an amorphous solid dispersion.
  • a method of manufacturing a pharmaceutical composition comprising an amorphous solid dispersion comprises one or more steps selected from (i) combining a solvent, a hydrophilic high-molecular weight material, and an API or a salt or solvate thereof thereby producing a combined mixture; (ii) contacting the combined mixture with an adsorbent; (iii) removing at least a portion of the solvent from the mixture, thereby producing an amorphous solid dispersion; and (iv) mixing the amorphous solid dispersion with one or more pharmaceutically acceptable excipients or carriers.
  • the API or a salt or solvate thereof is at least partially protonated.
  • a method of manufacturing a pharmaceutical composition comprising an amorphous solid dispersion, wherein the API is palbociclib.
  • the amorphous solid dispersion comprises a salt of palbociclib.
  • the amorphous solid dispersion comprises palbociclib mesylate.
  • the salt of palbociclib is formed in situ in the mixture.
  • a method of manufacturing a pharmaceutical composition comprising an amorphous solid dispersion, wherein the API is neratinib.
  • the amorphous solid dispersion comprises a salt of neratinib.
  • the amorphous solid dispersion comprises neratinib maleate.
  • the salt of neratinib is formed in situ in the mixture.
  • the method of manufacturing a pharmaceutical composition comprises concurrently combining a solvent, a hydrophilic high-molecular weight material, and an API or a salt or solvate thereof and contacting the combined mixture with an adsorbent; followed by removing the solvent (or a portion thereof) from the mixture.
  • the adsorbent can added into the mixture before, concurrently, or after any one of the API or the pharmaceutically acceptable salt or solvate thereof, the hydrophilic high-molecular weight material, and the solvent. In some embodiments, the adsorbent is added into the solvent.
  • the method of manufacturing a pharmaceutical composition comprises first combining a solvent, a hydrophilic high-molecular weight material, and an API or a salt or solvate thereof, and then contacting the resultant mixture with an adsorbent.
  • a method of manufacturing a pharmaceutical composition comprising an amorphous solid dispersion involves combining a solvent, a hydrophilic high-molecular weight material, and an API or a salt or solvate thereof; contacting the combined mixture with an adsorbent; removing the solvent (or a portion thereof) from the mixture, thereby producing an amorphous solid dispersion; and mixing the amorphous solid dispersion with one or more pharmaceutically acceptable excipients or carriers.
  • the adsorbent is silica.
  • one or more acids are combined with the API or a salt or solvate thereof in the mixture.
  • the one or more acids in the mixture comprise hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, and phosphoric acid, tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, acetic acid, oxalic acid, an aliphatic sulfonic acid, an aromatic sulfonic acid, or a combination thereof.
  • the method of manufacturing a pharmaceutical composition comprises combining a solvent, a hydrophilic high-molecular weight material, and an API or a salt or solvate thereof.
  • the combining comprises dissolving the API or a salt or solvent thereof, and the hydrophilic high-molecular weight material in the solvent.
  • the solvent comprises one or more organic solvents, water, or a combination thereof.
  • the solvent comprises water.
  • the solvent comprises water, wherein the ratio of the water to the API or a salt or solvate thereof is higher than 20: 1.
  • the solvent comprises water, wherein the ratio of the water to the API or a salt or solvate thereof is higher than 15: 1 or 10: 1.
  • the solvent comprises alcohol such as ethanol. In some embodiments, the combining comprises heating the mixture to a certain temperature, such as 30°C, 45°C, 50°C, or 60°C. In some embodiments, the combining comprises mixing the API with other components in the mixture.
  • the solvent comprises dichloromethane, water, alcohol, or acetone. In some embodiments, alcohol is methanol, ethanol, propanol, any isomer or propanol, or any mixture thereof. In some embodiments, the solvent comprises water and one or more alcohols such as methanol, ethanol, propanol, etc. In some embodiments, the solvent comprises water and acetone. In some embodiments, the solvent comprises dichloromethane. In some embodiments, the solvent comprises dichloromethane and one or more alcohols. In some embodiments, the solvent comprises dichloromethane and acetone.
  • the method of manufacturing comprises removing the solvent, or a portion thereof, to produce an amorphous solid dispersion.
  • removing the solvent, or a portion thereof, from the mixture comprises spray-drying or rotor evaporation.
  • the mixture is maintained at an elevated temperature, such as 40 °C during spray-dry.
  • the mixture is kept at room temperature, i.e., does not requiring any heating, during spray-dry.
  • the solvent is removed over a period of 2 hours to 96 hours. In some embodiments, the solvent is removed over a period of 24 hours to 72 hours.
  • a total solid content in the solution or mixture for spray drying is 5 % (w/v) or more. In some embodiments, a total solid content in the solution or mixture for spray drying is 2% (w/v) , 5% (w/v) , 10% (w/v) , 15% (w/v) , 20% (w/v) , 25% (w/v) , or 30% (w/v) or more. In some embodiments, an amorphous solid dispersion collected in a sample container in a spray dryer during spray drying is more than 50 % (w/w) .
  • an amorphous solid dispersion collected in a sample container in a spray dryer during spray drying is at least 20 %(w/w) , at least 30 % (w/w) , at least 40 % (w/w) , at least 50 % (w/w) , at least 60 % (w/w) , at least 70 % (w/w) , or at least 80 % (w/w) .
  • removing the solvent, or a portion thereof comprises spraying the mixture using a spray dryer.
  • the spray dryer configured to spray dry at a pressure of over 1.5 bar. In some embodiments, the spray dryer configured to spray dry at a pressure of over 2.0 to 2.5 bar.
  • the spray dryer configured to spray dry at a feed rate of over 1 mL/min. In some embodiments, the spray dryer configured to spray dry at a feed rate of about 5-12 mL/min. In some embodiments, the spray dryer configured to spray dry at a feed rate of about 5.8-9.8 mL/min. In some embodiments, the spray dryer is configured to produce particulates of an amorphous solid dispersion with a water content of less than 10%. In some embodiments, the spray dryer is configured to produce particulates of an amorphous solid dispersion with a water content of less than 8%.
  • removing the solvent, or a portion thereof comprises spraying the mixture onto the adsorbent. In some embodiments, the removing comprises drying in a fluid bed equipment. In some embodiments, the method further comprises compressing, milling or screening the amorphous solid dispersion with the one or more pharmaceutically acceptable excipients or carriers to form particulates.
  • the components of the amorphous dispersion are mixed and heated in a solvent, and the solvent is removed to form the amorphous solid dispersion.
  • the solvent is water.
  • the solvent is a polar organic solvent.
  • the solvent is a protic solvent.
  • the solvent is selected from water, n-butanol, n-propanol, isopropanol, formic acid, nitromethane, ethanol, methanol, acetic acid, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, dimethylformamide, acetonitrile, dimethyl sulfoxide, and any combination thereof.
  • the solvent is selected from water, n-butanol, n-propanol, isopropanol, formic acid, nitromethane, ethanol, methanol, acetic acid, and any combination thereof. In some embodiments, the solvent is selected from water, ethanol and isopropanol.
  • an amorphous solid dispersion is formed by first mixing tartaric acid and hydrochloric acid in water to form a clear solution. See Figure 2. Next, an API and copovidone is added to the acidic clear solution, and the mixture is mixed and heated to 45°C until a clear solution is formed. The clear solution comprising the API, acids and copovidone is then spray dried to form an amorphous solid dispersion. Following the formation of an amorphous solid dispersion, the amorphous solid dispersion is mixed with microcrystalline cellulose, lactose, about 50%of the total crospovidone used in the formulation, about 50%of the total magnesium stearate used in the formulation, and about 50%of the total silicon dioxide used in the formulation.
  • the mixture is then pressed into tablets.
  • the tablets are then milled and screened to form particles.
  • the particles are then mixed with about 50%of the total crospovidone used in the formulation, about 50%of the total magnesium stearate used in the formulation, and about 25%of the total silicon dioxide.
  • the mixture is then used to fill capsules.
  • hydrochloric acid is replaced with methanesulfonic acid.
  • the pharmaceutical composition wherein the pharmaceutical composition comprises: a) an amorphous solid dispersion, the amorphous solid dispersion comprising: (i) an active pharmaceutical ingredient (API) , or a pharmaceutically acceptable salt thereof; (ii) one or more interior acids; (iii) a hydrophilic high-molecular weight material; and (iv) optionally, an adsorbent; b) one or more exterior acids; and c) one or more pharmaceutically acceptable carriers or excipients, wherein the mass ratio of the one or more exterior acids to API is from about 0.1 to about 1: 1.
  • the amorphous solid dispersion (ASD) is formed with the one or more interior acids without coming into contact with the one or more exterior acids. Following formation of the ASD, the ASD, the one or more exterior acids, and the one or more pharmaceutically acceptable carriers or excipients are mixed used to fill capsules.
  • a capsule or tablet 301 having an inner matrix 302 and outer matrix 303, wherein the inner matrix 302 comprises an amorphous solid dispersion described herein.
  • the outer matrix 303 is in the space between the inner matrix particles. See Figure 3.
  • the outer matrix 303 may form boundaries between particulates of the inner matrix.
  • the outer matrix 303 may fill the space or form pockets between particulates of the inner matrix 302.
  • the outer matrix may envelope the majority of inner matrix 302 particles.
  • a capsule 401 having an inner matrix 402 and outer matrix 403, wherein the inner matrix comprises an amorphous solid dispersion described herein.
  • the capsule may be partially filled with the ingredients of the composition, and partially filled with a gas 404, such as air or nitrogen.
  • a gas 404 such as air or nitrogen.
  • the pharmaceutical compositions described in Figures 3 and 4 may be in capsule or table form, among other forms described herein.
  • Embodiment 1 An amorphous solid dispersion, wherein the amorphous solid dispersion comprises:
  • the molar ratio of the first acid to palbociclib is from 0.5: 1 to 5: 1, and wherein the weight ratio of the second acid to palbociclib is from 0.1: 1 to 10: 1
  • Embodiment 2 The amorphous solid dispersion of embodiment 1, wherein the salt of palbociclib comprises the first acid.
  • Embodiment 3 An amorphous solid dispersion, wherein the amorphous solid dispersion comprises:
  • the molar ratio of the first acid to palbociclib is from about 0.5: 1 to about 5: 1, and
  • weight ratio of the second acid to palbociclib is from about 0.1: 1 to about 10: 1.
  • Embodiment 4 The amorphous solid dispersion of any one of embodiments 1-3, wherein palbociclib is at least partially protonated.
  • Embodiment 5 The amorphous solid dispersion of any one of embodiments 1-4, wherein the salt of palbociclib is a monovalent palbociclib salt or a divalent palbociclib salt.
  • Embodiment 6 The amorphous solid dispersion of any one of embodiments 1-5, wherein the salt of palbociclib comprises:
  • Embodiment 7 The amorphous solid dispersion of embodiment 6, wherein the at least partially protonated palbociclib contains about 1%or more of pronated palbociclib.
  • Embodiment 8 The amorphous solid dispersion of embodiment 6, wherein the at least partially protonated palbociclib contains about 10%or more of pronated palbociclib.
  • Embodiment 9 The amorphous solid dispersion of embodiment 8, wherein the at least partially protonated palbociclib contains about 50%or more of pronated palbociclib.
  • Embodiment 10 The amorphous solid dispersion of any one of embodiments 1-9, wherein the first acid is oxalic acid, maleic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, an aliphatic sulfonic acid, or an aromatic sulfonic acid.
  • the first acid is oxalic acid, maleic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, an aliphatic sulfonic acid, or an aromatic sulfonic acid.
  • Embodiment 11 The amorphous solid dispersion of any one of embodiments 1-10, wherein the first acid has a pKa of at most 1.
  • Embodiment 12 The amorphous solid dispersion of any one of embodiments 1-11, wherein the first acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanesulfonic acid, butanesulfonic acid, benzylsulfonic acid, benzenesulfonic acid, tolylsulfonic acid, or naphthalenesulfonic acid.
  • the first acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanesulfonic acid, butanesulfonic acid, benzylsulfonic acid, benzenesulf
  • Embodiment 13 The amorphous solid dispersion of any one of embodiments 1-10, wherein the first acid is an aliphatic sulfonic acid.
  • Embodiment 14 The amorphous solid dispersion of embodiment 13, wherein the first acid is methanesulfonic acid.
  • Embodiment 15 The amorphous solid dispersion of any one of embodiments 1-10, wherein the first acid is maleic acid.
  • Embodiment 16 The amorphous solid dispersion of any one of embodiments 1-15, wherein the second acid has a pKa greater than 3.
  • Embodiment 17 The amorphous solid dispersion of any one of embodiments 1-15, wherein the second acid has a pKa of about 2 to about 6.
  • Embodiment 18 The amorphous solid dispersion of any one of embodiments 1-17, wherein the second acid is an inorganic acid.
  • Embodiment 19 The amorphous solid dispersion of any one of embodiments 1-17, wherein the second acid is an organic acid.
  • Embodiment 20 The amorphous solid dispersion of embodiment 19, wherein the second acid is tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, or acetic acid.
  • Embodiment 21 The amorphous solid dispersion of embodiment 20, wherein the second acid is tartaric acid.
  • Embodiment 22 The amorphous solid dispersion of any one of embodiments 1-21, wherein the molar ratio of the first acid to palbociclib is from about 0.5: 1 to about 3: 1.
  • Embodiment 23 The amorphous solid dispersion of any one of embodiments 1-22, wherein the molar ratio of the first acid to palbociclib is from about 1: 1 to about 1.5: 1.
  • Embodiment 24 The amorphous solid dispersion any one of embodiments 1-23, wherein a weight ratio of the second acid to palbociclib is from about 0.2: 1 to about 5: 1.
  • Embodiment 25 The amorphous solid dispersion of any one of embodiments 1-24, wherein a weight ratio of the second acid to palbociclib is from about 0.2: 1 to about 1.2: 1.
  • Embodiment 26 The amorphous solid dispersion of any one of embodiments 1-25, wherein the palbociclib is protonated on the pyridine nitrogen, the secondary piperazine nitrogen, or both.
  • Embodiment 27 The amorphous solid dispersion of any one of embodiments 1-26, wherein the at least partially protonated palbociclib is a reaction product of the first acid with palbociclib free base or a salt thereof.
  • Embodiment 28 The amorphous solid dispersion of any one of embodiment 1, wherein the amorphous solid dispersion comprises a salt of palbociclib, wherein the salt is a reaction product of palbociclib free base with the first acid.
  • Embodiment 29 The amorphous solid dispersion of embodiment 23, wherein the salt of palbociclib is formed in situ.
  • Embodiment 30 The amorphous solid dispersion of any one of embodiment 1, wherein the amorphous solid dispersion consists of palbociclib mesylate, tartaric acid, a hydrophilic high molecular weight material, and an optional adsorbent.
  • Embodiment 31 The amorphous solid dispersion of any one of embodiment 1, wherein the hydrophilic high-molecular weight material comprises vinylpyrrolidone-vinyl acetate copolymer (copovidone) , polyvinylpyrrolidone (PVP or povidone) , polyvinyl alcohol (PVA) , polysaccharide, hydroxypropyl methylcellulose (HPMC or hypromellose) , hydroxyethyl cellulose (HEC) , hydroxypropyl cellulose (HPC) , polyethylene oxide, hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) , sulfobutylether- ⁇ -cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS) , polyethylene glycol (PEG) , polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (PVAc-P
  • Embodiment 32 The amorphous solid dispersion of embodiment 31, wherein the hydrophilic high-molecular weight material is PVP, copovidone, HPMC, or a combination thereof.
  • Embodiment 33 The amorphous solid dispersion of any one of embodiments 1-31, wherein the hydrophilic high-molecular weight material comprises from about 10%to about 80%of a total weight of the amorphous solid dispersion.
  • Embodiment 34 The amorphous solid dispersion of any one of embodiments 1-33, wherein the hydrophilic high-molecular weight material comprises from about 20%to about 50%of a total weight of the amorphous solid dispersion.
  • Embodiment 35 The amorphous solid dispersion of any one of embodiments 1-34, comprising:
  • the salt of palbociclib is palbociclib mesylate present in an amount of 20%to 60%of a total weight of the amorphous solid dispersion
  • the second acid comprises tartaric acid present in an amount of 20%to 40%of a total weight of the amorphous solid dispersion
  • the hydrophilic high-molecular weight material is present in an amount of 20%to 40%of a total weight of the amorphous solid dispersion
  • hydrophilic high-molecular weight material is selected from HPMC, PVP, and copovidone.
  • Embodiment 36 The amorphous solid dispersion of any one of embodiments 1-35, comprising:
  • the salt of palbociclib is palbociclib mesylate present in an amount of 40%to 45%of a total weight of the amorphous solid dispersion
  • the second acid comprises tartaric acid present in an amount of 25%to 30%of a total weight of the amorphous solid dispersion
  • the hydrophilic high-molecular weight material is present in an amount of 25%to 30%of a total weight of the amorphous solid dispersion, wherein the hydrophilic high-molecular weight material is selected from HPMC, PVP, and copovidone.
  • Embodiment 37 The amorphous solid dispersion of any one of embodiments 1-36, comprising:
  • the salt of palbociclib is palbociclib mesylate present in an amount of 25%to 45%of a total weight of the amorphous solid dispersion
  • the first acid comprises methanesulfonic acid present in an amount of 1%to 15%of a total weight of the amorphous solid dispersion
  • the second acid comprises tartaric acid present in an amount of 20%to 40%of a total weight of the amorphous solid dispersion
  • the hydrophilic high-molecular weight material in an amount of 20%to 40%of a total weight of the amorphous solid dispersion, wherein the hydrophilic high-molecular weight material is selected from HPMC, PVP, and copovidone.
  • Embodiment 38 The amorphous solid dispersion any one of embodiments 1-37, further comprising an adsorbent present in the amorphous solid dispersion in an amount of about 5%to about 50%of a total weight of the amorphous solid dispersion.
  • Embodiment 39 The amorphous solid dispersion any one of embodiments 1-38, further comprising an adsorbent selected from silica, active carbon, magnesium aluminum silicate, diatomite, microcrystalline cellulose (MCC) , silicified microcrystalline cellulose (SMCC) , talc, sugar, and sugar alcohol.
  • an adsorbent selected from silica, active carbon, magnesium aluminum silicate, diatomite, microcrystalline cellulose (MCC) , silicified microcrystalline cellulose (SMCC) , talc, sugar, and sugar alcohol.
  • Embodiment 40 The amorphous solid dispersion of embodiment 39, wherein the adsorbent is silica.
  • Embodiment 41 The amorphous solid dispersion of any one of embodiments 1-40, comprising about 30-40 wt%palbociclib, about 5-10 wt%methanesulfonic acid, about 25-35 wt%tartaric acid and about 25-35 wt%hydroxypropylmethyl cellulose.
  • Embodiment 42 The amorphous solid dispersion of any one of embodiments 1-41, comprising 35.5 wt%palbociclib, 7.6 wt%methanesulfonic acid, 28.4 wt%tartaric acid and 28.4%wt%hydroxypropylmethyl cellulose.
  • Embodiment 43 An amorphous solid dispersion, wherein the amorphous solid dispersion comprises:
  • a molar ratio of the first acid to palbociclib is from about 0.5: 1 to about 3: 1, and
  • a weight ratio of the second acid to palbociclib is from about 0.2: 1 to about 1.5: 1.
  • Embodiment 44 The amorphous solid dispersion of embodiment 43, wherein palbociclib is at least partially protonated.
  • Embodiment 45 The amorphous solid dispersion of embodiment 43 or 44, wherein the salt of palbociclib is a monovalent palbociclib salt or a divalent palbociclib salt.
  • Embodiment 46 The amorphous solid dispersion of any one of embodiments 43-45, wherein the salt of palbociclib comprises:
  • Embodiment 47 The amorphous solid dispersion of embodiment 44, wherein the at least partially protonated palbociclib contains about 1%or more of pronated palbociclib.
  • Embodiment 48 The amorphous solid dispersion of embodiment 44, wherein the at least partially protonated palbociclib contains about 10%or more of pronated palbociclib.
  • Embodiment 49 The amorphous solid dispersion of embodiment 44, wherein the at least partially protonated palbociclib contains about 50%or more of pronated palbociclib.
  • Embodiment 50 The amorphous solid dispersion of any one of embodiments 43, wherein the first acid is oxalic acid, maleic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, an aliphatic sulfonic acid, or an aromatic sulfonic acid.
  • the first acid is oxalic acid, maleic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, an aliphatic sulfonic acid, or an aromatic sulfonic acid.
  • Embodiment 51 The amorphous solid dispersion of any one of embodiments 43-50, wherein the first acid has a pKa of at most 1.
  • Embodiment 52 The amorphous solid dispersion of any one of embodiments 43-51, wherein the first acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanesulfonic acid, butanesulfonic acid, benzylsulfonic acid, benzenesulfonic acid, tolylsulfonic acid, or naphthalenesulfonic acid.
  • the first acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanesulfonic acid, butanesulfonic acid, benzylsulfonic acid, benzenesul
  • Embodiment 53 The amorphous solid dispersion of any one of embodiments 43-52, wherein the first acid is an aliphatic sulfonic acid.
  • Embodiment 54 The amorphous solid dispersion of embodiment 53, wherein the first acid is methanesulfonic acid.
  • Embodiment 55 The amorphous solid dispersion of any one of embodiments 43-52, wherein the first acid is maleic acid.
  • Embodiment 56 The amorphous solid dispersion of any one of embodiments 43-55, wherein the first acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and nitric acid.
  • Embodiment 57 The amorphous solid dispersion of any one of embodiments 43-56, wherein the second acid has a pKa greater than 3.
  • Embodiment 58 The amorphous solid dispersion of any one of embodiments 43-56, wherein the second acid has a pKa of about 2 to about 6.
  • Embodiment 59 The amorphous solid dispersion of any one of embodiments 43-58, wherein the second acid is an inorganic acid.
  • Embodiment 60 The amorphous solid dispersion of any one of embodiments 43-58, wherein the second acid is an organic acid.
  • Embodiment 61 The amorphous solid dispersion of embodiment 60, wherein the second acid is selected from tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, and acetic acid.
  • Embodiment 62 The amorphous solid dispersion of embodiment 61, wherein the second acid is tartaric acid.
  • Embodiment 63 The amorphous solid dispersion of any one of embodiments 43-62, wherein the molar ratio of the first acid to palbociclib is from about 1: 1 to about 1.5: 1.
  • Embodiment 64 The amorphous solid dispersion of any one of embodiments 43-63, wherein a weight ratio of the second acid to palbociclib is from about 0.2: 1 to about 1.2: 1.
  • Embodiment 65 The amorphous solid dispersion of any one of embodiments 43-64, wherein the palbociclib is protonated on the pyridine nitrogen, the secondary piperazine nitrogen, or both.
  • Embodiment 66 The amorphous solid dispersion of any one of embodiments 43-65, wherein the at least partially protonated palbociclib is a reaction product of the first acid with palbociclib free base or a salt thereof.
  • Embodiment 67 The amorphous solid dispersion of any one of embodiments 43-66, wherein the amorphous solid dispersion comprises a salt of palbociclib, wherein the salt is a reaction product of palbociclib free base with the first acid.
  • Embodiment 68 The amorphous solid dispersion of embodiment 67, wherein the salt of palbociclib is formed in situ.
  • Embodiment 69 The amorphous solid dispersion of any one of embodiments 43-68, wherein the amorphous solid dispersion consists of palbociclib mesylate, tartaric acid, a hydrophilic high molecular weight material, and an optional adsorbent.
  • Embodiment 70 The amorphous solid dispersion of any one of embodiments 43-69, wherein the hydrophilic high-molecular weight material comprises vinylpyrrolidone-vinyl acetate copolymer (copovidone) , polyvinylpyrrolidone (PVP or povidone) , polyvinyl alcohol (PVA) , polysaccharide, hydroxypropyl methylcellulose (HPMC or hypromellose) , hydroxyethyl cellulose (HEC) , hydroxypropyl cellulose (HPC) , polyethylene oxide, hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) , sulfobutylether- ⁇ -cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS) , polyethylene glycol (PEG) , polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (P
  • Embodiment 71 The amorphous solid dispersion of embodiment 70, wherein the hydrophilic high-molecular weight material is PVP, copovidone, HPMC, or a combination thereof.
  • Embodiment 72 The amorphous solid dispersion of any one of embodiments 43-71, wherein the hydrophilic high-molecular weight material is present in from about 10%to about 80%of a total weight of the amorphous solid dispersion.
  • Embodiment 73 The amorphous solid dispersion of any one of embodiments 43-72, wherein the hydrophilic high-molecular weight material is present in from about 20%to about 50%of a total weight of the amorphous solid dispersion.
  • Embodiment 74 The amorphous solid dispersion of any one of embodiments 43-73, wherein:
  • the salt of palbociclib is palbociclib mesylate present in an amount of 20%to 60%of a total weight of the amorphous solid dispersion
  • the second acid comprises tartaric acid present in an amount of 20%to 40%of a total weight of the amorphous solid dispersion
  • the hydrophilic high-molecular weight material is present in 20%to 40%of a total weight of the amorphous solid dispersion, wherein the hydrophilic high-molecular weight material is selected from HPMC, PVP, and copovidone.
  • Embodiment 75 The amorphous solid dispersion of any one of embodiments 43-74, comprising:
  • palbociclib mesylate in an amount of about 40%to about 45%of a total weight of the amorphous solid dispersion
  • tartaric acid in an amount of about 25%to about 30%of a total weight of the amorphous solid dispersion
  • hydrophilic high-molecular weight material in an amount of about 25%to about 30%of a total weight of the amorphous solid dispersion, wherein the hydrophilic high-molecular weight material is selected from HPMC, PVP, and copovidone.
  • Embodiment 76 The amorphous solid dispersion of any one of embodiments 43-75, further comprising an adsorbent present in the amorphous solid dispersion in an amount of about 5%to about 50%of a total weight of the amorphous solid dispersion.
  • Embodiment 77 The amorphous solid dispersion of any one of embodiments 43-76, further comprising an adsorbent selected from silica, active carbon, magnesium aluminum silicate, diatomite, microcrystalline cellulose (MCC) , silicified microcrystalline cellulose (SMCC) , talc, sugar, and sugar alcohol.
  • an adsorbent selected from silica, active carbon, magnesium aluminum silicate, diatomite, microcrystalline cellulose (MCC) , silicified microcrystalline cellulose (SMCC) , talc, sugar, and sugar alcohol.
  • Embodiment 78 The amorphous solid dispersion of embodiment 77, wherein the adsorbent is silica.
  • Embodiment 79 The amorphous solid dispersion of any one of embodiments 43-78, comprising about 30-40 wt%palbociclib, about 5-10 wt%methanesulfonic acid, about 25-35 wt%tartaric acid and about 25-35 wt%hydroxypropylmethyl cellulose.
  • Embodiment 80 The amorphous solid dispersion of any one of embodiments 43-79, comprising 35.5 wt%palbociclib, 7.6 wt%methanesulfonic acid, 28.4 wt%tartaric acid and 28.4%wt%hydroxypropylmethyl cellulose.
  • Embodiment 81 An amorphous solid dispersion, wherein the amorphous solid dispersion comprises:
  • API active pharmaceutical ingredient
  • - is a single bond or a double bond
  • R 1 is C 1 -C 6 alkyl
  • R 3 is C 1 -C 8 alkoxy, C 3 -C 7 cycloalkyl, or C 3 -C 7 -heterocyclyl;
  • R 2 and R 4 are each independently hydrogen, halogen, C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 hydroxyalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, nitrile, nitro, -OR 10 , -SR 10 , -NR 10 R 11 , -N (O) R 10 R 11 , -P (O) (OR 10 ) (OR 11 ) , - (CR 10 R 11 ) m NR 12 R 13 , -COR 10 , - (CR 10 R 11 ) m C (O) R 12 , -CO 2 R 10 , -CONR 10 R 11 , -C (O) NR 10 SO 2 R 11
  • each of R 5 , R 6 , and R 7 is independently hydrogen, halogen, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -C 1 -C 8 alkoxy, -C 1 -C 8 alkoxyalkyl, -CN, -NO 2 , -OR 10 , -NR 10 R 11 , -CO 2 R 10 , -COR 10 , -S (O) n R 10 , -CONR 10 R 11 , -NR 10 COR 11 , -NR 10 SO 2 R 11 , -SO 2 NR 10 R 11 , or -P (O) (OR 10 ) (OR 11 ) ;
  • each of R 10 , R 11 , R 12 and R 13 is independently hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • - m is 0, 1, 2, 3, 4, 5, or 6;
  • - n 0, 1 or 2;
  • a molar ratio of the first acid to Formula (I) is from about 0.5: 1 to about 5: 1, and
  • a weight ratio of the second acid to Formula (I) is from about 0.1: 1 to about 10: 1.
  • Embodiment 82 The amorphous solid dispersion of embodiment 81, wherein the salt of Formula (I) comprises Formula (I) and the first acid.
  • Embodiment 83 The amorphous solid dispersion of embodiment 81 or 82, wherein represents a double bond.
  • Embodiment 84 The amorphous solid dispersion of any one of embodiments 81-83, wherein each of R 5 , R 6 , and R 7 is hydrogen.
  • Embodiment 85 The amorphous solid dispersion of any one of embodiments 81-84, wherein R 1 is methyl.
  • Embodiment 86 The amorphous solid dispersion of any one of embodiments 81-85, wherein R 2 is - (CO) CH 3 .
  • Embodiment 87 The amorphous solid dispersion of any one of embodiments 81-86 wherein R 3 is C 3 -C 7 cycloalkyl.
  • Embodiment 88 The amorphous solid dispersion of any one of embodiments 81-87, wherein R 3 is cyclopentyl.
  • Embodiment 89 The amorphous solid dispersion of any one of embodiments 81-88, wherein R 4 is C 3 -C 7 heterocycloalkyl.
  • Embodiment 90 The amorphous solid dispersion of any one of embodiments 81-89 wherein R 4 is 6-membered heterocycloalkyl containing 1 or 2 ring nitrogen atoms.
  • Embodiment 91 The amorphous solid dispersion of any one of embodiments 81-90, wherein R 4 is piperazinyl, piperidinyl, pyrrolidinyl, or morpholinyl.
  • Embodiment 92 The amorphous solid dispersion of embodiment 91, wherein R 4 is piperazinyl.
  • Embodiment 93 The amorphous solid dispersion of any one of embodiments 69-92, wherein the API comprises a pharmaceutically acceptable salt of Formula (I) , wherein the pharmaceutically acceptable salt of Formula (I) is a monovalent salt or a divalent salt.
  • Embodiment 94 The amorphous solid dispersion of any one of embodiments 69-93, wherein the API comprises a pharmaceutically acceptable salt of Formula (I) , wherein the pharmaceutically acceptable salt of Formula (I) comprises:
  • Embodiment 95 The amorphous solid dispersion of any one of embodiments 69-94, wherein the first acid is oxalic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, an aliphatic sulfonic acid, or an aromatic sulfonic acid.
  • the first acid is oxalic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, an aliphatic sulfonic acid, or an aromatic sulfonic acid.
  • Embodiment 96 The amorphous solid dispersion of any one of embodiments 69-95, wherein the first acid has a pKa smaller than 1.
  • Embodiment 97 The amorphous solid dispersion of any one of embodiments 69-96, wherein the first acid is methanesulfonic acid or benzenesulfonic acid.
  • Embodiment 98 The amorphous solid dispersion of any one of embodiments 69-97, wherein the API comprises mono-protonated API, di-protonated API, or both.
  • Embodiment 99 The amorphous solid dispersion of any one of embodiments 69-98, wherein the second acid has a pKa larger than 1.
  • Embodiment 100 The amorphous solid dispersion of any one of embodiments 69-99, wherein the second acid is an inorganic acid.
  • Embodiment 101 The amorphous solid dispersion of any one of embodiments 69-99, wherein the second acid is an organic acid.
  • Embodiment 102 The amorphous solid dispersion of embodiment 101, wherein the second acid is selected from tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, acetic acid, an aliphatic sulfonic acid, and an aromatic sulfonic acid.
  • the second acid is selected from tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, acetic acid, an aliphatic sulfonic acid, and an aromatic sulfonic acid.
  • Embodiment 103 The amorphous solid dispersion of embodiment 102, wherein the second acid is tartaric acid.
  • Embodiment 104 The amorphous solid dispersion of any one of embodiments 69-103, wherein the molar ratio of the first acid to API is from about 0.5: 1 to about 3: 1.
  • Embodiment 105 The amorphous solid dispersion of any one of embodiments 69-104, wherein the molar ratio of the first acid to API is from about 1: 1 to about 1.5: 1.
  • Embodiment 106 The amorphous solid dispersion of any one of embodiments 69-105, wherein a weight ratio of the second acid to API is from about 0.2: 1 to about 5: 1.
  • Embodiment 107 The amorphous solid dispersion of any one of embodiments 69-106, wherein a weight ratio of the second acid to API is from about 0.2: 1 to about 1.2: 1.
  • Embodiment 108 The amorphous solid dispersion of any one of embodiments 69-107, wherein the hydrophilic high-molecular weight material comprises vinylpyrrolidone-vinyl acetate copolymer (copovidone) , polyvinylpyrrolidone (PVP or povidone) , polyvinyl alcohol (PVA) , polysaccharide, hydroxypropyl methylcellulose (HPMC or hypromellose) , hydroxyethyl cellulose (HEC) , hydroxypropyl cellulose (HPC) , polyethylene oxide, hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) , sulfobutylether- ⁇ -cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS) , polyethylene glycol (PEG) , polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer
  • Embodiment 109 The amorphous solid dispersion of embodiment 108, wherein the hydrophilic high-molecular weight material is PVP, copovidone, HPMC, or a combination thereof.
  • Embodiment 110 The amorphous solid dispersion of any one of embodiments 69-109, wherein the hydrophilic high-molecular weight material comprises from about 10%to about 80%of a total weight of the amorphous solid dispersion.
  • Embodiment 111 The amorphous solid dispersion of any one of embodiments 69-110, wherein the hydrophilic high-molecular weight material comprises from about 30%to about 50%of a total weight of the amorphous solid dispersion.
  • Embodiment 112 The amorphous solid dispersion of any one of embodiments 69-111, wherein:
  • the API is a mesylate salt in an amount of 20%to 60%of a total weight of the amorphous solid dispersion
  • the second acid comprises tartaric acid present in an amount of 20%to 40%of a total weight of the amorphous solid dispersion
  • the hydrophilic high-molecular weight material in an amount of 20%to 40%of a total weight of the amorphous solid dispersion, wherein the hydrophilic high-molecular weight material is selected from HPMC, PVP, and copovidone.
  • Embodiment 113 The amorphous solid dispersion of any one of embodiments 69-112, wherein:
  • the API wherein the API is present in 25%to 45%of a total weight of the amorphous solid dispersion
  • the first acid comprises methanesulfonic acid present in an amount of 1%to 15%of a total weight of the amorphous solid dispersion
  • the second acid comprises tartaric acid present in an amount of 20%to 40%of a total weight of the amorphous solid dispersion
  • the hydrophilic high-molecular weight material in an amount of 20%to 40%of a total weight of the amorphous solid dispersion, wherein the hydrophilic high-molecular weight material is selected from HPMC, PVP, and copovidone.
  • Embodiment 114 The amorphous solid dispersion of any one of embodiments 69-113, further comprising an adsorbent present in the amorphous solid dispersion in an amount of about 5%to about 50%of a total weight of the amorphous solid dispersion.
  • Embodiment 115 The amorphous solid dispersion of any one of embodiments 69-114, further comprising an adsorbent selected from silica, active carbon, magnesium aluminum silicate, diatomite, microcrystalline cellulose (MCC) , silicified microcrystalline cellulose (SMCC) , talc, sugar, and sugar alcohol.
  • an adsorbent selected from silica, active carbon, magnesium aluminum silicate, diatomite, microcrystalline cellulose (MCC) , silicified microcrystalline cellulose (SMCC) , talc, sugar, and sugar alcohol.
  • Embodiment 116 The amorphous solid dispersion of embodiment 114, wherein the absorbent is silica.
  • Embodiment 117 The amorphous solid dispersion of any one of embodiments 69-116, comprising about 30-40 wt%palbociclib, about 5-10 wt%methanesulfonic acid, about 25-35 wt%tartaric acid and about 25-35 wt%hydroxypropylmethyl cellulose.
  • Embodiment 118 The amorphous solid dispersion of any one of embodiments 69-117, comprising 35.5 wt%palbociclib, 7.6 wt%methanesulfonic acid, 28.4 wt%tartaric acid and 28.4%wt%hydroxypropylmethyl cellulose.
  • Embodiment 119 An amorphous solid dispersion, wherein the amorphous solid dispersion comprises:
  • Embodiment 120 The amorphous solid dispersion of embodiment 119, wherein the pharmaceutically acceptable salt of neratinib is a monovalent neratinib salt or a divalent neratinib salt.
  • Embodiment 121 The amorphous solid dispersion of embodiment 120, wherein the pharmaceutically acceptable salt of neratinib comprises:
  • Embodiment 122 The amorphous solid dispersion of embodiment 119 or 120, wherein the hydrophilic high-molecular weight material comprises vinylpyrrolidone-vinyl acetate copolymer (copovidone) , polyvinylpyrrolidone (PVP or povidone) , polyvinyl alcohol (PVA) , polysaccharide, hydroxypropyl methylcellulose (HPMC or hypromellose) , hydroxyethyl cellulose (HEC) , hydroxypropyl cellulose (HPC) , polyethylene oxide, hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) , sulfobutylether- ⁇ -cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS) , polyethylene glycol (PEG) , polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (PVAc
  • Embodiment 123 The amorphous solid dispersion of embodiment 122, wherein the hydrophilic high-molecular weight material is PVP, copovidone, HPMC, or a combination thereof.
  • Embodiment 124 The amorphous solid dispersion of any one of embodiments 119-123, wherein the hydrophilic high-molecular weight material is present in from about 10%to about 60%of a total weight of the amorphous solid dispersion.
  • Embodiment 125 An amorphous solid dispersion, wherein the amorphous solid dispersion comprises:
  • a molar ratio of the one or more acids to the API is from about 0.1: 1 to about 20: 1.
  • Embodiment 126 The amorphous solid dispersion of embodiment 125 wherein the pharmaceutically acceptable salt of neratinib is a monovalent neratinib salt or a divalent neratinib salt.
  • Embodiment 127 The amorphous solid dispersion of embodiment 126, wherein the pharmaceutically acceptable salt of neratinib comprises:
  • Embodiment 128 The amorphous solid dispersion of any one of embodiments125-127, wherein the two or more pharmaceutically acceptable acids are organic acids.
  • Embodiment 129 The amorphous solid dispersion of any one of embodiments 125-128, wherein the organic acids are selected from oxalic acid, maleic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, acetic acid, an aliphatic sulfonic acid, and an aromatic sulfonic acid.
  • the organic acids are selected from oxalic acid, maleic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, acetic acid, an aliphatic sulfonic acid, and an aromatic sulfonic acid.
  • Embodiment 130 The amorphous solid dispersion of embodiment 129, wherein the aliphatic sulfonic acid or the aromatic sulfonic acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanesulfonic acid, butanesulfonic acid, benzylsulfonic acid, benzenesulfonic acid, tolylsulfonic acid, or naphthalenesulfonic acid.
  • the aliphatic sulfonic acid or the aromatic sulfonic acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanes
  • Embodiment 131 The amorphous solid dispersion of any one of embodiments 125-130, wherein the first acid is an aliphatic sulfonic acid.
  • Embodiment 132 The amorphous solid dispersion of embodiment 131, wherein the first acid is methanesulfonic acid.
  • Embodiment 133 The amorphous solid dispersion of any one of embodiments 125-132, wherein the first acid is maleic acid.
  • Embodiment 134 The amorphous solid dispersion of any one of embodiments 125-133, wherein the molar ratio of the two or more pharmaceutically acceptable acids to neratinib is from about 2: 1 to about 10: 1.
  • Embodiment 135. The amorphous solid dispersion of any one of embodiments 125-134, wherein the molar ratio of acid to neratinib is from about 2: 1 to about 5: 1.
  • Embodiment 136 The amorphous solid dispersion of any one of embodiments 125-135, wherein the molar ratio of the two or more pharmaceutically acceptable acids to neratinib is from about 3: 1 to about 4: 1.
  • Embodiment 137 The amorphous solid dispersion of any one of embodiments 125-136, wherein the salt of neratinib is formed in situ with at least one of the two or more pharmaceutically acceptable acids.
  • Embodiment 138 The amorphous solid dispersion of any one of embodiments 125-137, wherein the amorphous solid dispersion comprises neratinib maleate, neratinib mesylate, or a combination thereof.
  • Embodiment 139 The amorphous solid dispersion of any one of embodiments 125-138, wherein the hydrophilic high-molecular weight material comprises vinylpyrrolidone-vinyl acetate copolymer (copovidone) , polyvinylpyrrolidone (PVP or povidone) , polyvinyl alcohol (PVA) , polysaccharide, hydroxypropyl methylcellulose (HPMC or hypromellose) , hydroxyethyl cellulose (HEC) , hydroxypropyl cellulose (HPC) , polyethylene oxide, hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) , sulfobutylether- ⁇ -cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS) , polyethylene glycol (PEG) , polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer
  • Embodiment 140 The amorphous solid dispersion of embodiment 139, wherein the hydrophilic high-molecular weight material is PVP, copovidone, HPMC, or a combination thereof.
  • Embodiment 141 The amorphous solid dispersion of any one of embodiments 125-140, wherein the hydrophilic high-molecular weight material is present in from about 10%to about 60%of a total weight of the amorphous solid dispersion.
  • Embodiment 142 The amorphous solid dispersion of any one of embodiments 125-141, wherein the hydrophilic high-molecular weight material is present in from about 20%to about 50%of a total weight of the amorphous solid dispersion.
  • Embodiment 143 The amorphous solid dispersion of any one of embodiments 125-141, comprising:
  • neratinib maleate in an amount of about 20%to about 60%of a total weight of the amorphous solid dispersion
  • HPMC HPMC, PVP, or copovidone in an amount of about 20%to about 40%of a total weight of the amorphous solid dispersion.
  • Embodiment 144 An amorphous solid dispersion, wherein the amorphous solid dispersion comprises:
  • API active pharmaceutical ingredient
  • R 1 is halogen
  • R 2 is a pyridinyl, thiophene, pyrimidine, thiazole, or phenyl, each of which is optionally substituted with up to three substituents;
  • - R 3 is -O-or -S-;
  • R 4 is C 1-3 alkyl or C 1-3 heteroalkyl
  • R 5 is ethyl or methyl
  • - n is 0 or 1;
  • Embodiment 145 The amorphous solid dispersion of embodiment 144, wherein R 1 is chlorine.
  • Embodiment 146 The amorphous solid dispersion of embodiment 144 or 145, wherein R 2 is pyridinyl.
  • Embodiment 147 The amorphous solid dispersion of any one of embodiments 144-146, wherein R 3 is -O-.
  • Embodiment 148 The amorphous solid dispersion of any one of embodiments 144-147, wherein R 4 is methyl.
  • Embodiment 149 The amorphous solid dispersion of any one of embodiments 144-148, wherein R 5 is ethyl.
  • Embodiment 150 The amorphous solid dispersion of any one of embodiments 144-149, wherein n is 1.
  • Embodiment 151 The amorphous solid dispersion of any one of embodiments 144-150, wherein the compound of Formula (II) is a maleate salt.
  • Embodiment 152 The amorphous solid dispersion of any one of embodiments 144-151, wherein the one or more acids comprise a first acid and a second acid.
  • Embodiment 153 The amorphous solid dispersion of embodiment 152, wherein the first acid has a pKa of at most 2 and the second acid has a pKa greater than 2.
  • Embodiment 154 The amorphous solid dispersion of embodiment 152, wherein the first acid has a pKa of at most 1, and second acid has a pKa greater than 1.
  • Embodiment 155 The amorphous solid dispersion of embodiment 152, wherein the molar ratio of the first acid to API is from about 0.5: 1 to about 5: 1 and wherein the weight ratio of the second acid to API is from about 0.1: 1 to about 10: 1.
  • Embodiment 156 The amorphous solid dispersion of embodiment 152, wherein the API is a pharmaceutically acceptable salt of Formula (II) , wherein the pharmaceutically acceptable salt of Formula (II) is a monovalent salt or a divalent salt.
  • Embodiment 157 The amorphous solid dispersion of embodiment 156, wherein the API is a pharmaceutically acceptable salt of Formula (II) , wherein the pharmaceutically acceptable salt of Formula (II) comprises:
  • Embodiment 158 An amorphous solid dispersion, wherein the amorphous solid dispersion comprises:
  • API is at least partially protonated
  • the API has a logP of at least 2;
  • a molar ratio of the one or more acids to the API is from about 0.1: 1 to about 20: 1.
  • Embodiment 159 The amorphous solid dispersion of embodiment 158, wherein the API is selected from the group consisting of neratinib, erlotinib, sulfacetamide, Sulfachlorpyridazine, sulfadiazine, sulfadimethoxine, sulfaguanidine, sulfamerazine, sulfamethazine, sulfamethizole, sulfamethoxazole, sulfathiazole, chlortetracycline, demeclocycline, doxycycline, meclocycline, oxytetracycline, tetracycline, ciprofloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, fleroxacin, flumequine, lomefloxacin, marbofloxacin, nalidixic acid, norfloxa
  • Embodiment 160 The amorphous solid dispersion of embodiment 158 or 159, wherein the protonated API has a pKa of about 2 to about 10.
  • Embodiment 161 The amorphous solid dispersion of any one of embodiments 158-160, wherein the protonated API has a pKa of about 3 to about 9.
  • Embodiment 162 The amorphous solid dispersion of any one of embodiments 158-161, wherein the unprotonated API has a solubility of less than 0.1 mg/mL.
  • Embodiment 163 The amorphous solid dispersion of any one of embodiments 158-162, wherein the unprotonated API has a solubility of less than 0.05 mg/mL.
  • Embodiment 164 The amorphous solid dispersion of any one of embodiments 158-163, wherein the unprotonated API has a solubility of less than 0.01 mg/mL.
  • Embodiment 165 The amorphous solid dispersion of any one of embodiments 158-164, wherein the API is gefitinib, erlotinib, or neratinib, or a salt or solvate thereof.
  • Embodiment 166 The amorphous solid dispersion of any one of embodiments 158-165, wherein a ratio of a solubility of the protonated API to a solubility of the API as a free base is at least 10: 1 in water.
  • Embodiment 167 The amorphous solid dispersion of any one of embodiments 158-166, wherein a ratio of a solubility of the protonated API to a solubility of the API as a free base is at least 100: 1 in water.
  • Embodiment 168 The amorphous solid dispersion of any one of embodiments 158-167, wherein the API comprises mono-protonated API, di-protonated API, or both.
  • Embodiment 169 The amorphous solid dispersion of any one of embodiments 158-168, wherein the one or more acids are partially or completely ionized acid.
  • Embodiment 170 The amorphous solid dispersion of any one of embodiments 158-169, wherein the one or more acids comprise an organic acid.
  • Embodiment 171 The amorphous solid dispersion of embodiment 170, wherein the organic acid is oxalic acid, maleic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, and acetic acid an aliphatic sulfonic acid, or an aromatic sulfonic acid.
  • the organic acid is oxalic acid, maleic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, and acetic acid an aliphatic sulfonic acid, or an aromatic sulfonic acid.
  • Embodiment 172 The amorphous solid dispersion of embodiment 171, wherein an aliphatic sulfonic acid or an aromatic sulfonic acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanesulfonic acid, butanesulfonic acid, benzylsulfonic acid, benzenesulfonic acid, tolylsulfonic acid, or naphthalenesulfonic acid.
  • an aliphatic sulfonic acid or an aromatic sulfonic acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanes
  • Embodiment 173 The amorphous solid dispersion of embodiment 158, wherein the one or more acids comprise an inorganic acid.
  • Embodiment 174 The amorphous solid dispersion of embodiment 173, wherein the inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, and phosphoric acid.
  • the inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, and phosphoric acid.
  • Embodiment 175. The amorphous solid dispersion of embodiment 174, wherein the one or more acids comprise HCl.
  • Embodiment 176 The amorphous solid dispersion of embodiment 171, wherein the one or more acids comprise tartaric acid.
  • Embodiment 177 The amorphous solid dispersion of any one of embodiments 158-176, wherein the one or more acids comprise a first acid and a second acid.
  • Embodiment 178 The amorphous solid dispersion of embodiment 177, wherein the first acid has a pKa of at most 2 and the second has a pKa greater than 2.
  • Embodiment 179 The amorphous solid dispersion of embodiment 177, wherein the first acid has a pKa of at most 1, and second acid has a pKa greater than 1.
  • Embodiment 180 The amorphous solid dispersion of embodiment 177, wherein the first acid is HCl and the second acid is tartaric acid.
  • Embodiment 181 The amorphous solid dispersion of embodiment 177, wherein the first acid is methanesulfonic acid and the second acid is tartaric acid.
  • Embodiment 182 The amorphous solid dispersion of embodiment 177, wherein the first acid is an organic or inorganic acid, and the second acid is an organic acid.
  • Embodiment 183 The amorphous solid dispersion of embodiment 177, wherein the first acid has a pKa equal to or smaller than 1, and second acid has a pKa larger than 1.
  • Embodiment 184 The amorphous solid dispersion of any one of embodiments 177-183, wherein the API is at least partially protonated and is a reaction product of the first acid with a free base of the API.
  • Embodiment 185 The amorphous solid dispersion of any one of embodiments 158-184, wherein the amorphous solid dispersion comprises a salt of the API, and wherein the salt is formed in situ.
  • Embodiment 186 The amorphous solid dispersion of any one of embodiments 158-185, wherein the amorphous solid dispersion comprises a mesylate salt of the API or a hydrochloride salt of the API.
  • Embodiment 187 The amorphous solid dispersion of any one of embodiments 158-186, wherein a molar ratio of the one or more acids to the API is from about 1: 1 to about 4: 1.
  • Embodiment 188 The amorphous solid dispersion of any one of embodiments 158-187, wherein the hydrophilic high-molecular weight material comprises vinylpyrrolidone-vinyl acetate copolymer (copovidone) , polyvinylpyrrolidone (PVP or povidone) , polyvinyl alcohol (PVA) , polysaccharide, hydroxypropyl methylcellulose (HPMC or hypromellose) , hydroxyethyl cellulose (HEC) , hydroxypropyl cellulose (HPC) , polyethylene oxide, hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) , sulfobutylether- ⁇ -cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS) , polyethylene glycol (PEG) , polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer
  • Embodiment 189 The amorphous solid dispersion of embodiment 188, wherein the hydrophilic high-molecular weight material is PVP, copovidone, HPMC, or a combination thereof.
  • Embodiment 190 The amorphous solid dispersion of any one of embodiments 158-189, wherein the hydrophilic high-molecular weight material is present in from about 10%to about 80%of a total weight of the amorphous solid dispersion.
  • Embodiment 191 The amorphous solid dispersion of any one of embodiments 158-190, wherein the hydrophilic high-molecular weight material is present in from about 30%to about 50%of a total weight of the amorphous solid dispersion.
  • Embodiment 192 The amorphous solid dispersion of any one of embodiments 158-191, wherein:
  • the API is present in an amount of about 25%to about 45%of a total weight of the amorphous solid dispersion
  • one or more acids comprises tartaric acid present in an amount of about 20%to about 40%of a total weight of the amorphous solid dispersion
  • copovidone in an amount of about 20%to about 40%of a total weight of the amorphous solid dispersion.
  • Embodiment 193 The amorphous solid dispersion of any one of embodiments 158-192, wherein:
  • a salt of the API comprising about 40%to about 60%of a total weight of the amorphous solid dispersion, wherein the salt of the API comprises a cation that is the protonated API and an anion from the one or more acids, and wherein the one or more acids are ionized;
  • copovidone in an amount of about 40%to about 60%of a total weight of the amorphous solid dispersion.
  • Embodiment 194 The amorphous solid dispersion of any one of embodiments 158-193, wherein the one or more acids is ionized HCl.
  • Embodiment 195 The amorphous solid dispersion of any one of embodiments 158-194, further comprising an absorbent present in the amorphous solid dispersion in an amount of about 5%to about 50%of a total weight of the amorphous solid dispersion.
  • Embodiment 196 The amorphous solid dispersion of any one of embodiments 158-195, further comprising an adsorbent selected from silica, active carbon, magnesium aluminum silicate, diatomite, microcrystalline cellulose (MCC) , silicified microcrystalline cellulose (SMCC) , talc, sugar, and sugar alcohol.
  • an adsorbent selected from silica, active carbon, magnesium aluminum silicate, diatomite, microcrystalline cellulose (MCC) , silicified microcrystalline cellulose (SMCC) , talc, sugar, and sugar alcohol.
  • Embodiment 197 The amorphous solid dispersion of embodiment 196, wherein the adsorbent is silica.
  • Embodiment 198 An amorphous solid dispersion, wherein the amorphous solid dispersion comprises:
  • an active pharmaceutical ingredient (API) , a pharmaceutically acceptable salt of the API, or any combination thereof, wherein the pharmaceutically acceptable salt of the API comprises the API and the first acid,
  • the molar ratio of the first acid to API is from about 0.5: 1 to about 5: 1, and
  • weight ratio of the second acid to API is from about 0.1: 1 to about 10: 1.
  • Embodiment 199 The amorphous solid dispersion of embodiment 198, wherein the pharmaceutically acceptable salt of the API is a monovalent salt or a divalent salt.
  • Embodiment 200 The amorphous solid dispersion of embodiment 199, wherein the pharmaceutically acceptable salt of the API comprises:
  • Embodiment 201 The amorphous solid dispersion of any one of embodiments 198-200, wherein the molar ratio of the first acid to API is from about 0.5: 1 to about 3: 1, and the weight ratio of the second acid to API is from about 0.2: 1 to about 1.5: 1.
  • Embodiment 202 The amorphous solid dispersion of any one of embodiments 198-201, wherein the first acid is oxalic acid, maleic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, an aliphatic sulfonic acid, or an aromatic sulfonic acid.
  • the first acid is oxalic acid, maleic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, an aliphatic sulfonic acid, or an aromatic sulfonic acid.
  • Embodiment 203 The amorphous solid dispersion of embodiment 202, wherein the first acid is an aliphatic sulfonic acid.
  • Embodiment 204 The amorphous solid dispersion of embodiment 202 or 203, wherein the first acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanesulfonic acid, butanesulfonic acid, benzylsulfonic acid, benzenesulfonic acid, tolylsulfonic acid, or naphthalenesulfonic acid.
  • the first acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanesulfonic acid, butanesulfonic acid, benzylsulfonic acid, benzenesulf
  • Embodiment 205 The amorphous solid dispersion of embodiment 204, wherein the first acid is methanesulfonic acid.
  • Embodiment 206 The amorphous solid dispersion of any one of embodiments 198-202, wherein the first acid is maleic acid.
  • Embodiment 207 The amorphous solid dispersion of any one of embodiments 198-201, wherein the second acid is an inorganic acid.
  • Embodiment 208 The amorphous solid dispersion of any one of embodiments 198-201, wherein the second acid is an organic acid.
  • Embodiment 209 The amorphous solid dispersion of embodiment 208, wherein the second acid is selected from tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, and acetic acid.
  • the second acid is selected from tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, and acetic acid.
  • Embodiment 210 The amorphous solid dispersion of any one of embodiments 198-209, wherein the molar ratio of the first acid to API is from about 0.8: 1 to about 2: 1.
  • Embodiment 211 The amorphous solid dispersion of any one of embodiments 198-210, wherein the molar ratio of the first acid to API is from about 1: 1 to about 1.5: 1.
  • Embodiment 212 The amorphous solid dispersion of any one of embodiments 198-211, wherein a weight ratio of the second acid to API is from about 0.2: 1 to about 1.2: 1.
  • Embodiment 213 The amorphous solid dispersion of any one of embodiments 198-212, wherein the amorphous solid dispersion comprises a salt of the API, wherein the salt is a reaction product of the API free base with the first acid.
  • Embodiment 214 The amorphous solid dispersion of embodiment 213, wherein the salt of the API is formed in situ.
  • Embodiment 215. The amorphous solid dispersion of any one of embodiments 198-214, wherein the hydrophilic high-molecular weight material comprises vinylpyrrolidone-vinyl acetate copolymer (copovidone) , polyvinylpyrrolidone (PVP or povidone) , polyvinyl alcohol (PVA) , polysaccharide, hydroxypropyl methylcellulose (HPMC or hypromellose) , hydroxyethyl cellulose (HEC) , hydroxypropyl cellulose (HPC) , polyethylene oxide, hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) , sulfobutylether- ⁇ -cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS) , polyethylene glycol (PEG) , polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer
  • Embodiment 216 The amorphous solid dispersion of embodiment 215, wherein the hydrophilic high-molecular weight material is PVP, copovidone, HPMC, or a combination thereof.
  • Embodiment 217 The amorphous solid dispersion of any one of embodiments 198-216, wherein the hydrophilic high-molecular weight material is present in from about 10%to about 80%of a total weight of the amorphous solid dispersion.
  • Embodiment 218 The amorphous solid dispersion of any one of embodiments 198-217, wherein the hydrophilic high-molecular weight material is present in from about 20%to about 50%of a total weight of the amorphous solid dispersion.
  • Embodiment 219. The amorphous solid dispersion of any one of embodiments 198-218, comprising:
  • the API in an amount of about 20%to about 60%of a total weight of the amorphous solid dispersion
  • hydrophilic high-molecular weight material in an amount of about 20%to about 40%of a total weight of the amorphous solid dispersion.
  • Embodiment 220 The amorphous solid dispersion of any one of embodiments 198-219, comprising:
  • the API in an amount of about 40%to about 45%of a total weight of the amorphous solid dispersion
  • hydrophilic high-molecular weight material in an amount of about 25%to about 30%of a total weight of the amorphous solid dispersion.
  • Embodiment 221 The amorphous solid dispersion of any one of embodiments 198-220, further comprising an adsorbent present in the amorphous solid dispersion in an amount of about 5%to about 50%of a total weight of the amorphous solid dispersion.
  • Embodiment 222 The amorphous solid dispersion of embodiment 221, wherein the adsorbent is selected from silica, active carbon, magnesium aluminum silicate, diatomite, microcrystalline cellulose (MCC) , silicified microcrystalline cellulose (SMCC) , talc, sugar, and sugar alcohol.
  • the adsorbent is selected from silica, active carbon, magnesium aluminum silicate, diatomite, microcrystalline cellulose (MCC) , silicified microcrystalline cellulose (SMCC) , talc, sugar, and sugar alcohol.
  • Embodiment 223 The amorphous solid dispersion of embodiment 222, wherein the adsorbent is silica.
  • Embodiment 224 A pharmaceutical composition, wherein the pharmaceutical composition comprises:
  • Embodiment 225 The pharmaceutical composition of embodiment 224, wherein the one or more pharmaceutically acceptable carriers or excipients comprise a filler, a binder, a disintegrating agent, a lubricant, an adsorbent, an acid, or a combination thereof.
  • Embodiment 226 The pharmaceutical composition of embodiment 224 or 225, wherein the one or more pharmaceutically acceptable carriers or excipients comprise microcrystalline cellulose, lactose, crospovidone, magnesium stearate, silicon dioxide, an organic acid, or a combination thereof.
  • Embodiment 227 The pharmaceutical composition of any one of embodiments 224-226, wherein:
  • the amorphous solid dispersion is present in an amount of about 50%to about 95%of a total weight of the pharmaceutical composition
  • microcrystalline cellulose is present in an amount of about 1%to about 12%of a total weight of the pharmaceutical composition
  • crospovidone is present in an amount of about 1%to about 10%of a total weight of the pharmaceutical composition
  • magnesium stearate is present in an amount of about 0.2%to about 5%of a total weight of the pharmaceutical composition
  • silica is present in an amount of about 0.2%to about 5%of a total weight of the pharmaceutical composition
  • an organic acid is present in an amount of about 5%to about 20%of a total weight of the pharmaceutical composition.
  • Embodiment 228 The pharmaceutical composition of any one of embodiments 224-227, wherein:
  • the amorphous solid dispersion is present in an amount of about 70%to about 80%of a total weight of the pharmaceutical composition
  • amorphous solid dispersion comprises:
  • the first acid in an amount of about 1%to about 15%of a total weight of the amorphous solid dispersion
  • the second acid in an amount of about 20%to about 40%of a total weight of the amorphous solid dispersion
  • the hydrophilic high-molecular weight material in an amount of about 20%to about 40%of a total weight of the amorphous solid dispersion
  • microcrystalline cellulose is present in an amount of about 5%to about 6%of a total weight of the pharmaceutical composition
  • crospovidone is present in an amount of about 4.5%to about 5.5%of a total weight of the pharmaceutical composition
  • magnesium stearate is present in an amount of about 0.5%to about 1.5%of a total weight of the pharmaceutical composition
  • silica is present in an amount of about 0.5%to about 1.5%of a total weight of the pharmaceutical composition
  • an organic acid is present in an amount of about 11%to about 13%of a total weight of the pharmaceutical composition.
  • Embodiment 229. The pharmaceutical composition of any one of embodiments 224-228, wherein:
  • the amorphous solid dispersion is present in an amount of about 75.7%of a total weight of the pharmaceutical composition, wherein the amorphous solid dispersion comprises:
  • i. palbociclib in an amount of about 35.5%of a total weight of the amorphous solid dispersion
  • HPMC in an amount of about 28.4%of a total weight of the amorphous solid dispersion
  • microcrystalline cellulose is present in an amount of about 5.5%of a total weight of the pharmaceutical composition
  • crospovidone is present in an amount of about 5%of a total weight of the pharmaceutical composition
  • magnesium stearate is present in an amount of about 1%of a total weight of the pharmaceutical composition
  • silica is present in an amount of about 1%of a total weight of the pharmaceutical composition
  • tartaric acid is present in an amount of about 11.8%of a total weight of the pharmaceutical composition.
  • Embodiment 230 The pharmaceutical composition of any one of embodiments 224-229, wherein:
  • a) palbociclib is present in an amount of equivalent to 125 mg of palbociclib free base
  • methanesulfonic acid is present in an amount of about 26.7 mg
  • c) tartaric acid is present in an amount of about 155 mg
  • HPMC is present in an amount of about 100 mg
  • microcrystalline cellulose is present in an amount of about 25.5 mg;
  • crospovidone is present in an amount of about 23.3 mg
  • magnesium stearate is present in an amount of about 4.7 mg.
  • silica is present in an amount of about 4.7 mg.
  • Embodiment 23 The pharmaceutical composition of any one of embodiments 224-229, wherein palbociclib is present in an amount of equivalent to about 75 mg, about 100 mg, or about 125 mg of palbociclib free base.
  • Embodiment 232 A pharmaceutical composition, wherein the pharmaceutical composition comprises:
  • an amorphous solid dispersion comprising:
  • an active pharmaceutical ingredient i. an active pharmaceutical ingredient (API) , a pharmaceutically acceptable salt thereof, or any combination thereof;
  • mass ratio of the one or more exterior acids to API is from about 0.1 to about 1: 1.
  • Embodiment 233 The pharmaceutical composition of embodiment 232, wherein the pharmaceutically acceptable salt of the API is a monovalent salt or a divalent salt.
  • Embodiment 234 The amorphous solid dispersion of embodiment 233, wherein the pharmaceutically acceptable salt of the API comprises:
  • Embodiment 235 The pharmaceutical composition of any one of embodiments 232-234, wherein the mass ratio of the one or more exterior acids to API is from about 0.2 to about 0.7: 1.
  • Embodiment 236 The pharmaceutical composition of any one of embodiments 232-235, wherein the mass ratio of the one or more exterior acids to API is from about 0.3 to about 0.5: 1.
  • Embodiment 237 The pharmaceutical composition of any one of embodiments 232-236, wherein a molar ratio of the one or more interior acids to the API is from about 0.1: 1 to about 20: 1.
  • Embodiment 238 The pharmaceutical composition of any one of embodiments 232-237, wherein a molar ratio of the one or more interior acids to the API is from about 0.1: 1 to about 10: 1.
  • Embodiment 239. The pharmaceutical composition of any one of embodiments 232-238, wherein a molar ratio of the one or more interior acids to the API is from about 1: 1 to about 5: 1.
  • Embodiment 240 The pharmaceutical composition of any one of embodiments 232-239, wherein the one or more exterior acids comprises one or more organic acid.
  • Embodiment 241 The pharmaceutical composition of any one of embodiments 232-240, wherein the one or more exterior acids is oxalic acid, maleic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, and acetic acid an aliphatic sulfonic acid, or an aromatic sulfonic acid.
  • the one or more exterior acids is oxalic acid, maleic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, and acetic acid an aliphatic sulfonic acid, or an aromatic sulfonic acid.
  • Embodiment 242 The pharmaceutical composition of embodiment 241, wherein an aliphatic sulfonic acid or an aromatic sulfonic acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanesulfonic acid, butanesulfonic acid, benzylsulfonic acid, benzenesulfonic acid, tolylsulfonic acid, or naphthalenesulfonic acid.
  • an aliphatic sulfonic acid or an aromatic sulfonic acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanesulfonic acid, but
  • Embodiment 243 The pharmaceutical composition of any one of embodiments 232-242, wherein the one or more exterior acids comprises a first acid and a second acid.
  • Embodiment 244 The pharmaceutical composition of embodiment 243 , wherein the first acid is an aliphatic sulfonic acid.
  • Embodiment 245. The pharmaceutical composition of embodiment 244, wherein the first acid is methanesulfonic acid.
  • Embodiment 246 The pharmaceutical composition of embodiment 243, wherein the first acid is maleic acid.
  • Embodiment 247 The pharmaceutical composition of any one of embodiments 232-241, wherein the one or more exterior acids is tartaric acid.
  • Embodiment 248 The pharmaceutical composition of any one of embodiments 232-239, wherein the one or more exterior acids comprises one or more inorganic acid.
  • Embodiment 249. The pharmaceutical composition of embodiment 248, wherein the inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, and phosphoric acid.
  • Embodiment 250 The pharmaceutical composition of any one of embodiments 232-249, wherein the protonated API has a pKa of about 2 to about 10.
  • Embodiment 251 The pharmaceutical composition of any one of embodiments 232-250, wherein the protonated API has a pKa of about 3 to about 9.
  • Embodiment 252 The pharmaceutical composition of any one of embodiments 232-251, wherein the unprotonated API has a solubility of less than 0.1 mg/mL.
  • Embodiment 253 The pharmaceutical composition of any one of embodiments 232-252, wherein the unprotonated API has a solubility of less than 0.05 mg/mL.
  • Embodiment 254 The pharmaceutical composition of any one of embodiments 232-253, wherein the unprotonated API has a solubility of less than 0.01 mg/mL.
  • Embodiment 255 The pharmaceutical composition of any one of embodiments 232-254, wherein the API is palbociclib, gefitinib, erlotinib, or neratinib, or a salt or solvate thereof.
  • Embodiment 256 The pharmaceutical composition of any one of embodiments 232-255, wherein the one or more interior acids in the amorphous solid dispersion comprises an organic acid.
  • Embodiment 257 The pharmaceutical composition of embodiment 256, wherein the organic acid is oxalic acid, maleic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, and acetic acid an aliphatic sulfonic acid, or an aromatic sulfonic acid.
  • the organic acid is oxalic acid, maleic acid, trichloroacetic acid, dichloroacetic acid, trifluoroacetic acid, tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid, malic acid, and acetic acid an aliphatic sulfonic acid, or an aromatic sulfonic acid.
  • Embodiment 258 The pharmaceutical composition of embodiment 257, wherein an aliphatic sulfonic acid or an aromatic sulfonic acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanesulfonic acid, butanesulfonic acid, benzylsulfonic acid, benzenesulfonic acid, tolylsulfonic acid, or naphthalenesulfonic acid.
  • an aliphatic sulfonic acid or an aromatic sulfonic acid is methanesulfonic acid, methanedisulfonic acid, triflic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 2-mercapto-1-ethansulfonic acid, propanesulfonic acid,
  • Embodiment 259. The pharmaceutical composition of any one of embodimens 232-257, wherein the one or more interior acids comprise tartaric acid.
  • Embodiment 260 The pharmaceutical composition of any one of embodiments 232-257, wherein the one or more interior acids comprises maleic acid.
  • Embodiment 261 The pharmaceutical composition of any one of embodiments 232-255, wherein the one or more interior acids in the amorphous solid dispersion comprises an inorganic acid.
  • Embodiment 262 The pharmaceutical composition of embodiment 261, wherein the inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, and phosphoric acid.
  • the inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, and phosphoric acid.
  • Embodiment 263 The pharmaceutical composition of any one of embodiments 232-255, wherein the one or more interior acids comprise hydrochloric acid.
  • Embodiment 264 The pharmaceutical composition of any one of embodiments 232-263, wherein the one or more interior acids comprise a first acid and a second acid.
  • Embodiment 265. The pharmaceutical composition of embodiment 264, wherein the first acid has a pKa of at most 2 and the second acid has a pKa greater than 2.
  • Embodiment 266 The pharmaceutical composition of embodiment 265, wherein the first acid has a pKa of at most 1, and second acid has a pKa greater than 1.
  • Embodiment 267 The pharmaceutical composition of embodiment 265, wherein the first acid is HCl and the second acid is tartaric acid.
  • Embodiment 268 The pharmaceutical composition of embodiment 265, wherein the first acid is an organic or inorganic acid, and the second acid is an organic acid.
  • Embodiment 269. The pharmaceutical composition embodiment 264, wherein the first acid is an aliphatic sulfonic acid.
  • Embodiment 270 The pharmaceutical composition of embodiment 269, wherein the first acid is methanesulfonic acid.
  • Embodiment 271 The pharmaceutical composition of embodiment 264, wherein the first acid is maleic acid.
  • Embodiment 272 The pharmaceutical composition of any one of embodiments 264-270, wherein the first acid is methanesulfonic acid and the second acid is tartaric acid.
  • Embodiment 273 The pharmaceutical composition of any one of embodiments 232-272, wherein the hydrophilic high-molecular weight material comprises vinylpyrrolidone-vinyl acetate copolymer (copovidone) , polyvinylpyrrolidone (PVP or povidone) , polyvinyl alcohol (PVA) , polysaccharide, hydroxypropyl methylcellulose (HPMC or hypromellose) , hydroxyethyl cellulose (HEC) , hydroxypropyl cellulose (HPC) , polyethylene oxide, hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) , sulfobutylether- ⁇ -cyclodextrin, hydroxypropyl methylcellulose acetate succinate (HPMCAS) , polyethylene glycol (PEG) , polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (PVAc-PV
  • Embodiment 274 The pharmaceutical composition of embodiment 273, wherein the hydrophilic high-molecular weight material is PVP, copovidone, HPMC, or a combination thereof.
  • Embodiment 275 A method of manufacturing a pharmaceutical composition comprising an amorphous solid dispersion, the method comprising:
  • Embodiment 276 The method of embodiment 275, wherein the removing comprises spray-drying or rotor evaporation.
  • Embodiment 277 The method of embodiment 275 or 276, wherein the adsorbent is silica.
  • Embodiment 279. The method of any one of embodiments 275-278, wherein the combining comprises dissolving the API or a salt or solvent thereof, and the hydrophilic high-molecular weight material in the solvent.
  • Embodiment 280 The method of any one of embodiments 275-279, wherein the solvent comprises one or more organic solvents, or a combination thereof.
  • Embodiment 281. The method of any one of embodiments 275-280, wherein the solvent comprises alcohol.
  • Embodiment 282. The method of any one of embodiments 275-281, wherein the solvent is water.
  • Embodiment 283 The method of any one of embodiments 275-282, wherein a weight ratio of the solvent to the API or a salt or solvate thereof is higher than 10: 1.
  • Embodiment 284 The method of any one of embodiments 275-283, further comprising mixing the amorphous solid dispersion with one or more pharmaceutically acceptable excipients or carriers.
  • Embodiment 285. The method of any one of embodiments 275-284, further comprising compressing, milling or screening the amorphous solid dispersion with the one or more pharmaceutically acceptable excipients or carriers to form particulates.
  • Embodiment 286 A method of manufacturing an amorphous solid dispersion comprising an amorphous solid dispersion, the method comprising:
  • the molar ratio of the first acid to palbociclib is from about 0.5: 1 to about 5: 1, and
  • weight ratio of the second acid to palbociclib is from about 0.1: 1 to about 10: 1
  • Embodiment 287 The method of embodiment 286, further comprising adding an adsorbent into the mixture.
  • Embodiment 288 The method of embodiment 286 or 287, wherein the removing comprises spray-drying or rotor evaporation.
  • Embodiment 289. The method of any one of embodiments 286-288, wherein the removing comprises spraying the mixture onto an adsorbent.
  • Embodiment 290 The method of embodiment 289, wherein the adsorbent is silica.
  • Embodiment 291. The method of any one of embodiments 286-290, wherein the removing comprises drying in a fluid bed equipment.
  • Embodiment 292 The method of any one of embodiments 286-291, wherein the combining comprises dissolving the API or a salt or solvent thereof, and the hydrophilic high-molecular weight material in the solvent.
  • Embodiment 293 The method of any one of embodiments 286-292, wherein the solvent comprises one or more organic solvents, or a combination thereof.
  • Embodiment 294. The method of any one of embodiments 286-293, wherein the solvent comprises alcohol.
  • Embodiment 295. The method of any one of embodiments 286-294, wherein the solvent is water.
  • Embodiment 296 The method of any one of embodiments 286-295, wherein a weight ratio of the solvent to the total weight of the first acid, second acid, hydrophilic high-molecular weight material, and palbociclib or a salt of palbociclib is less than 20: 1.
  • Embodiment 297 The method of any one of embodiments 286-296, further comprising mixing the amorphous solid dispersion with one or more pharmaceutically acceptable excipients or carriers.
  • Embodiment 298 The method of any one of embodiments 286-297, further comprising compressing, milling or screening the amorphous solid dispersion with the one or more pharmaceutically acceptable excipients or carriers to form particulates.
  • Embodiment 299. A method of treating a disease or condition, comprising administering to a subject in need thereof a pharmaceutical composition or an amorphous solid dispersion of any one of embodiments 1 to 274, preferably wherein the disease or condition is cancer.
  • Embodiment 300 The method of embodiment 299, wherein the amorphous solid dispersion or the pharmaceutical composition comprises palbociclib or a salt thereof.
  • Embodiment 301 The method of embodiment 300, wherein the palbociclib or a salt thereof is administered with or without food.
  • Embodiment 302. The method of embodiment 299, wherein the method comprises administering palbociclib once daily in an amount equivalent to 125 mg of palbociclib free base per day for 21 days.
  • Embodiment 303 The method of any one of embodiments 299-302, wherein the cancer is a solid cancer.
  • Embodiment 304 The method of any one of embodiments 299-302, wherein the cancer is breast cancer.
  • Embodiment 305 The method of embodiment 304, wherein the cancer is metastatic breast cancer.
  • Embodiment 306 The method of embodiment 305, wherein the cancer is hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer.
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • Embodiment 307 The method of any one of embodiments 300-306, further comprising administering an aromatase inhibitor as initial endocrine based therapy in postmenopausal women.
  • Embodiment 308 The method of embodiment 307, wherein the aromatase inhibitor is anastrozole, exemestane, or letrozole.
  • Embodiment 309 The method of any one of embodiments 300-306, further comprising administering fulvestrant, wherein the subject is a women with disease progression following endocrine therapy.
  • Embodiment 310 Use of the pharmaceutical composition or the amorphous solid dispersion of any one of embodiments 1 to 274 for the treatment of cancer in a subject.
  • Embodiment 311 The use of embodiment 310, wherein the amorphous solid dispersion or the pharmaceutical composition comprises palbociclib or a salt thereof.
  • Embodiment 312 The use of embodiment 311, wherein the palbociclib or a salt thereof is administered with or without food.
  • Embodiment 313 The use of embodiment 311, wherein palbociclib is administered once daily in an amount equivalent to 125 mg of palbociclib free base per day for 21 days.
  • Embodiment 314 The use of embodiment 311, wherein the cancer is a solid cancer.
  • Embodiment 315 The use of embodiment 311, wherein the cancer is breast cancer.
  • Embodiment 316 The use of embodiment 315, wherein the cancer is metastatic breast cancer.
  • Embodiment 317 The use of embodiment 316, wherein the cancer is hormone receptor (HR) -positive, human epidermal growth factor receptor 2 (HER2) -negative advanced or metastatic breast cancer.
  • HR hormone receptor
  • HER2 human epidermal growth factor receptor 2
  • Embodiment 318 The use of embodiment 311, wherein the pharmaceutical composition or the amorphous solid dispersion is used in combination with an aromatase inhibitor, and wherein the aromatase inhibitor is an initial endocrine based therapy in postmenopausal women.
  • Embodiment 319 The use of embodiment 311, wherein the aromatase inhibitor is anastrozole, exemestane, or letrozole.
  • Embodiment 320 The use of embodiment 311, wherein the pharmaceutical composition or the amorphous solid dispersion is used in combination with fulvestrant, wherein the subject is a women with disease progression following endocrine therapy.
  • Embodiment 32 The method of embodiment any one of embodiments 299-309, wherein the Cmax value of the API does not vary for more than 5%, 10%, 15%, 20%, 30%, 40%or 50%when the pharmaceutical compositions is administered in a fed or fasted state.
  • amorphous solid dispersions comprising an active pharmaceutical ingredient, one or more acids, and a hydrophilic high-molecular weight material.
  • the amorphous solid dispersions were prepared via spray drying or vacuum drying. Preparation by vacuum drying was typically utilized for small, bench scale preparation. Spray drying techniques were utilized for intermediate and large scale preparations.
  • Example 1 Formulation of Small Scale Compositions of Palbociclib Amorphous Solid Dispersions (ASD)
  • the active pharmaceutical ingredient (palbociclib) , one or more acids, optional additional excipients, and hydrophilic high molecular weight polymer were dissolved in a solvent or solvent mixture at a room temperature and optionally heated and/or sonicated to form a clear solution.
  • the solution was sparged with dinitrogen gas while being stirred and heated above 35 °C to remove excess water. Heating, sparging, and stirring were halted when the solution became gelatinous.
  • the vessel containing the gel was placed into a vacuum dryer and dried overnight at 40 °C and removed the next day to yield an amorphous solid dispersion.
  • Table 1 to Table 2 list the compositions of some of the amorphous solid dispersions that have been prepared by the bench top spray drying technique above. Dissolution of the amorphous solid dispersion systems SD-1 to SD-8 are shown in Figure 1.

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