CN114085203A - Dapagliflozin composition - Google Patents
Dapagliflozin composition Download PDFInfo
- Publication number
- CN114085203A CN114085203A CN202111552021.0A CN202111552021A CN114085203A CN 114085203 A CN114085203 A CN 114085203A CN 202111552021 A CN202111552021 A CN 202111552021A CN 114085203 A CN114085203 A CN 114085203A
- Authority
- CN
- China
- Prior art keywords
- dapagliflozin
- starch
- cellulose
- crystal
- sodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a dapagliflozin glycine eutectic compound which can form a stable dapagliflozin preparation, is easy to be biologically utilized and can be further processed to form a stable composition. Compared with dapagliflozin base, the novel crystal of dapagliflozin disclosed by the invention is more stable, better in solubility and better in processing performance, and is convenient to prepare into various dosage forms.
Description
Technical Field
The present invention relates to pharmaceutical compositions comprising co-crystals of dapagliflozin and one or more pharmaceutically acceptable excipients, methods of preparing the same, and methods of treating diabetes using the pharmaceutical compositions.
Background
Dapagliflozin is an orally active SGLT2 inhibitor and is disclosed in U.S. patent No.6,515,117, having the chemical name (2S,3R,4R,5S,6R) -2- [ 4-chloro-3- (4-ethoxyphenyl) benzene ] -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol and the chemical structural formula shown in fig. 1. Commercial formulations of dapagliflozin contain as active ingredient a propylene glycol (propylene glycol) -hydrate solvate of dapagliflozin. The active ingredient is crystalline in nature.
U.S. Pat. No.6,515,117 discloses dapagliflozin compounds. U.S. patent No.7,919,598 discloses (S) -propylene glycol solvate of dapagliflozin and a method for preparing the same. U.S. patent nos. 7,851,502, 8,221,786, and 8,361,972 disclose pharmaceutical compositions comprising dapagliflozin or dapagliflozin propylene glycol hydrate and a defined amount of a particular excipient. U.S. patent No.8,221,786 further discloses pharmaceutical compositions in the form of raw material granules comprising dapagliflozin propylene glycol hydrate and a defined amount of an excipient.
PCT patent WO 2012/163546 discloses pharmaceutical compositions comprising cyclodextrin and dapagliflozin, preferably as an inclusion complex.
PCT patent WO2015128853a1 discloses that dapagliflozin base is hygroscopic. It absorbs moisture and forms sticky lumps that are difficult to process and handle, which may ultimately lead to content uniformity problems in the formulation. The low solubility and stability of dapagliflozin base compared to its solvate may result in poor bioavailability of the drug.
The european original developer astrikon evaluation report EMA/689976/2012, which uses crystalline dapagliflozin propylene glycol hydrate, clearly mentions that the drug loading of dapagliflozin is low and that a uniform distribution of dapagliflozin in the premix is critical to achieving reproducible tablet levels. The main development challenges are: poor flowability, aggregation and stickiness of the active substance. Target low dose: content uniformity may be affected. The active substance is susceptible to oxidative degradation in the presence of excipients and moisture.
The dapagliflozin form described in U.S. Pat. No.6,515,117 is amorphous and unstable (very hygroscopic, easily forming a gelatinous consistency).
U.S. patent nos. 7,851,502 and 8,221,786 disclose pharmaceutical compositions comprising dapagliflozin Propylene Glycol (PG) hydrate.
PCT patent WO2008/002824 discloses crystalline solvates and complexes of dapagliflozin, namely (S) -propylene glycol ((S) -PG) hydrate (form SC-3), (R) -propylene glycol ((R) -PG) hydrate (SD-3 type), EtOH dihydrate (SA-I type), Ethylene Glycol (EG) dihydrate (SB-2 type), 1: 2L-proline complex (type 3), 1: 1L-proline complex (type 6), 1: 1L-proline hemihydrate (H.5-2 type), and 1: 1L-phenylalanine complex (type 2).
Due to drug loading below 25.0%, there is still an unmet need for a solid state form of dapagliflozin with good physicochemical properties, ideal bioavailability, and favorable pharmaceutical parameters (e.g. good flowability and excellent content uniformity).
Accordingly, there is a need to provide a stable form of dapagliflozin formulation that is readily bioavailable and that can be further processed to form a stable composition. The inventors of the present invention found that the novel crystals of dapagliflozin of the present invention are more stable, better soluble, and better processable than dapagliflozin base. In addition, the novel dapagliflozin crystal provided by the invention can be conveniently prepared into various dosage forms.
Disclosure of Invention
The new crystalline forms of the compounds may have physical properties that are different from and superior to those of the other crystalline forms. These properties include filling characteristics such as molar volume, density, and hygroscopicity; thermodynamic properties such as melting temperature, vapor pressure, and solubility; kinetic properties such as dissolution rate and stability under various storage conditions; surface characteristics such as surface area, wettability, interfacial tension and shape; mechanical properties such as hardness, tensile strength, compressibility, handling, flow and mixing; and filtration properties. Changes in any of these properties may affect the chemical and pharmaceutical processing of the compounds and their bioavailability, and may often make the new forms advantageous for pharmaceutical and medical use.
The present invention is based, in part, on the non-obvious discovery that the novel forms disclosed herein have advantageous physicochemical properties that make them more conducive to the processing of pharmaceuticals.
In contrast, the novel co-crystal forms of the present invention have sufficient stability characteristics to be particularly useful in a variety of different formulations for pharmaceutical applications.
The invention also includes various methods of preparing the pharmaceutical compositions and methods of treating diabetes by administering the pharmaceutical compositions. The present invention relates to pharmaceutical compositions comprising a novel dapagliflozin co-crystal and one or more pharmaceutically acceptable excipients. The co-crystal comprises dapagliflozin and a carrier, wherein the dapagliflozin is dispersed or dissolved in the carrier.
The present invention relates to a novel crystalline form of (2S,3r.4r.5s,6R) -2-4-chloro-3- (4-ethoxybenzyl) phenyl ] -6- (hydroxymethyl) tetrahydro-2H-pyran 3,4, 5-triol (dapagliflozin), i.e. a co-crystal comprising dapagliflozin and glycine. These forms are referred to herein as "dapagliflozin glycine co-crystals, dapagliflozin new crystal forms".
The novel crystalline forms of the present invention are distinct from and superior to the amorphous and dapagliflozin crystalline forms described in the prior art and patents.
The invention further relates to pharmaceutical compositions comprising the crystalline dapagliflozin co-crystal form of the invention and a pharmaceutically acceptable carrier and to the use thereof in the treatment of conditions and disorders in which dapagliflozin is therapeutically effective, such as type 2 diabetes.
The present invention further relates to methods of preparing the novel crystalline forms of dapagliflozin of the present invention.
In some embodiments, the dapagliflozin glycine co-crystal is characterized by an X-ray powder diffraction pattern substantially as shown in figures 3 a-d.
The dapagliflozin glycine co-crystal of the present invention is further characterized by the FTIR patterns shown in fig. 2 a-d.
The dapagliflozin glycine co-crystal of the invention is further characterized by the TGA profile shown in figure 4.
As used herein, the term "dapagliflozin" refers to dapagliflozin base, the chemical structural formula of which is shown in fig. 1. Dapagliflozin base is hygroscopic, less stable and less soluble than its solvate. It can rapidly absorb moisture, degrade, discolor and cause adhesion problems. Furthermore, the absorption of moisture leads to the formation of lumps, which may ultimately lead to content uniformity problems in the dosage form.
Thus, the pharmaceutical composition of the present invention is preferably prepared in the absence of water.
The term "co-crystal" refers, among other things, to a crystalline material composed of two or more distinct solids at room temperature, each having distinct physical characteristics.
A pharmaceutical co-crystal is defined as a crystal comprising two or more discrete neutral molecules in a stoichiometric ratio and held together by non-covalent interactions (e.g., hydrogen bonds, van der waals forces, and pi-pi stacking interactions), wherein at least one component is an API and the others are pharmaceutically acceptable components.
In 2016, the FDA revised guidelines describe co-crystals as "crystalline materials made of two or more different molecules bound together by non-ionic and non-covalent bonds within the same crystal lattice".
In 2018, the FDA described pharmaceutical co-crystals as "crystalline materials composed of two or more different molecules, one of which is an API, bound by non-ionic and non-covalent bonds in a defined stoichiometric ratio within the same crystal lattice". A coformer is "a component that interacts with the API in a lattice in a non-ionic manner, is not a solvent (including water), and is generally non-volatile".
The European Medicines Agency (EMA) defines a co-crystal as a "homogeneous (single-phase) crystal structure composed of two or more components in a stoichiometric ratio, in which the arrangement in the crystal lattice is not based on ionic bonds (e.g., salts)".
These pioneering works underscore the role of crystal engineering and supramolecular synthons in drug-based co-crystal design, encouraging the development of co-crystal approaches to improve drug performance.
The use of amino acids as co-formers in the co-amorphous formation has been extensively studied. It has been demonstrated that stability and dissolution profiles of APIs with solubility issues can be improved. Amino acids can be used as coformers because they have amino and carboxyl groups that can act as donors and acceptors for hydrogen bonding.
Besides being a natural compound with low risk, amino acids are mostly chiral compounds, so that they are widely used in the pharmaceutical industry as potential co-formers to form chiral co-crystals and possibly create new co-crystal subclasses. Due to its zwitterionic form, it is called a zwitterionic co-crystal.
It has surprisingly been found that when the Active Pharmaceutical Ingredient (API) and the selected co-crystal former are allowed to form a co-crystal, the resulting co-crystal may improve the performance of the free form API compared to the API in the same sample, in particular with respect to at least one of the following parameters: solubility, dissolution, bioavailability, stability, Cmax, Tmax, processability, more sustained therapeutic plasma concentrations, hygroscopicity, crystallization of amorphous compounds, reduced information diversity (including polymorphism and crystal habit), changes in morphology or crystal habit, and the like. The novel co-crystal forms of dapagliflozin in the present application have improved physicochemical properties, including high stability and lower hygroscopicity, compared to the free (amorphous) forms known in the art.
The invention also comprises a pharmaceutical composition of the novel crystal form and one or more pharmaceutical acceptable excipients, namely a pharmaceutical preparation formed by the pharmaceutical composition.
The term "pharmaceutically acceptable excipient" as used herein includes diluents, binders, disintegrants, lubricants, glidants, stabilizers, surfactants, dissolution enhancers, coloring agents, flavoring agents, and mixtures thereof.
Suitable diluents are selected from the following: anhydrous lactose such as lactose and lactose monohydrate; cellulosics such as microcrystalline cellulose, co-processed microcrystalline cellulose and powdered cellulose; starches, such as pregelatinized starch, corn starch, rice starch, potato starch, and wheat starch; sugar alcohols such as mannitol, sorbitol, xylitol and erythritol; inorganic salts such as calcium carbonate, calcium phosphate, calcium sulfate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, dihydrate calcium hydrogen phosphate, and tricalcium phosphate; and mixtures thereof.
The diluent may act as a binder. Suitable binders are selected from the group consisting of povidone, copovidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, gum arabic, tragacanth gum, sorbitol, glucose, sucrose, lactose, mannitol, gelatin, pullulan, sodium alginate, propylene glycol, polyvinyl alcohol, corn starch, modified corn starch, pregelatinized starch, methacrylate esters, carboxyvinyl polymers, waxes, and mixtures thereof. Suitable disintegrants are selected from croscarmellose sodium, hydroxypropyl cellulose, crospovidone, low substituted hydroxypropyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, gums, alginic acid or alginates, starches, corn starch, pregelatinized starch, modified starches, sodium starch glycolate, carboxymethyl starch, polyacrylates and mixtures thereof.
Suitable lubricants are selected from stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, polyethylene glycol, talc, hydrogenated vegetable oils, fatty acids, waxes and mixtures thereof.
Suitable glidants or anti-adherents are selected from talc, silicon dioxide, colloidal silicon dioxide (colloidal anhydrous silicon dioxide), calcium silicate, magnesium silicate, hydrated silicon dioxide and mixtures thereof.
Suitable stabilizers are selected from: cellulose derivatives such as hydroxypropylmethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, sodium carboxymethylcellulose and calcium carboxymethylcellulose; vinyl polymers such as polyvinylpyrrolidone, copovidone, and polyvinyl alcohol; polyethylene glycol; block copolymers of ethylene oxide and/or propylene oxide; gums, such as xanthan gum, gum arabic and/or derivatives thereof; pectin; an alginate; missing; tragacanth and/or a derivative thereof; carrageenan; agar and/or derivatives thereof; polysaccharides from microbial sources; starch; arabinogalactans; galactomannan; (ii) a glucan; and mixtures thereof. The stabilizer may also act as a crystallization inhibitor.
Suitable surfactants are selected from sodium lauryl sulfate, ammonium lauryl sulfate, benzalkonium chloride, alkyl poly (ethylene oxide), copolymers of poly (ethylene oxide) and poly (propylene oxide), commercially known as poloxamers or poloxamines, polyvinyl alcohol (PVA), fatty alcohols, polyoxyethylene alkyl ethers, polyoxyethylene alkylaryl ethers, polyethylene glycol fatty acid esters, alkylene glycol fatty acid monoesters, sucrose fatty acid esters, sorbitan fatty acid monoesters, sorbitol monolaurate(s) ((s))
20 or
80) Polyoxyethylene sorbitan fatty acid esters (polysorbates), and mixtures thereof.
Suitable solubilizers are selected from the group consisting of sodium lauryl sulfate, polyethylene glycol, propylene glycol, glycerol monostearate, glycerol behenate, triglycerides, monohydric alcohols, higher alcohols, dimethyl sulfoxide, dimethylformamide, N-dimethylacetamide, N-methyl-2-pyrrolidone, N- (2-hydroxyethyl) pyrrolidone, 2-pyrrolidone, and mixtures thereof.
Suitable coloring and flavoring agents are selected from FDA approved coloring and flavoring agents for oral administration.
The composition of the present invention may be in the form of caplets, pills, mini-tablets, granules, pills, tablets or capsules. The pharmaceutical composition of the present invention may also be dry granulated.
Suitable film-forming polymers are selected from: cellulose derivatives such as methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and ethyl cellulose; vinyl polymers such as polyvinylpyrrolidone; an acrylic polymer; andmixtures thereof. Alternatively, commercially available coating materials comprising film-forming polymers sold under various trade names, for example,
can be used for coating.
The coating additives include one or more of plasticizers, glidants or flow modifiers, lubricants, colorants, and opacifiers.
The composition of the invention is used for treating diabetes. The pharmaceutical compositions of the present invention may be administered in combination with other antidiabetics.
Drawings
FIG. 1 is the chemical structural formula of dapagliflozin;
FIG. 2a is an infrared spectrum of dapagliflozin hydrate, glycine and the new crystal form of dapagliflozin prepared in the invention, respectively, from top to bottom, as measured by a Fourier transform infrared absorption spectrometer (FTIR); wherein the abscissa is wavenumber (wavenumber) and unit cm-1The ordinate is the transmittance (transmittance), expressed in%; as can be seen from FIG. 2, the characteristic peaks of the novel crystal form of the invention in an FTIR chart are 3171cm-1、2361cm-1And 1012cm-1This is not seen in both dapagliflozin and glycine carriers, which reveals that dapagliflozin and glycine form a novel crystalline form of the invention;
FIGS. 2b-2d are separate spectra of the respective FTIR plots of FIG. 2 a;
FIG. 3a is an XRD pattern of the new crystal form of dapagliflozin, dapagliflozin hydrate and glycine prepared in the present invention, respectively, from top to bottom, wherein the abscissa is 2 θ and the ordinate is pulse counts (counts); as can be seen from fig. 3, the characteristic 2 θ values of the novel crystalline form of the present invention lack the following characteristic peaks of dapagliflozin and glycine: 9.656 +/-0.2 degrees, 10.876 +/-0.2 degrees, 15.414 +/-0.2 degrees, 17.461 +/-0.2 degrees, 32.338 +/-0.2 degrees, 33.182 +/-0.2 degrees, 34.470 +/-0.2 degrees, 35.902 +/-0.2 degrees and 38.225 +/-0.2 degrees; the existence or the lack of the characteristic peak represents a new crystal form, and the new crystal form does not have the characteristic peak, so that the new crystal form is brand new and is different from dapagliflozin and glycine;
figures 3b, 3c, 3d are separate spectra for each XRD pattern of figure 3 a;
FIG. 4 shows thermogravimetric curves of a new dapagliflozin crystal form, a dapagliflozin hydrate and glycine prepared by the invention, wherein the weight loss rate of the new crystal form is 2.8862% +/-0.2%, which is different from that of the dapagliflozin hydrate and glycine; also, as can be seen from fig. 4, the weight loss curves are also different;
fig. 5a is an optical microscope photograph of dapagliflozin propylene glycol monohydrate as a control crystalline form, from which it can be seen that the crystalline form of dapagliflozin has a sharp needle-like morphology, which deteriorates its flowability and is not suitable for production processes with large fluctuations in process parameters;
fig. 5b is an optical microscope photograph of the novel crystalline form of dapagliflozin-glycine of the present invention, from which it can be seen that the novel crystalline form of the present invention has a more rounded structure, which results in improved flowability and processability.
Detailed Description
In order that those skilled in the art will better understand the invention and thus more clearly define the scope of the invention as claimed, it is described in detail below with respect to certain specific embodiments thereof. It should be noted that the following is only a few embodiments of the present invention, and the specific direct description of the related structures is only for the convenience of understanding the present invention, and the specific features do not of course directly limit the scope of the present invention. Such alterations and modifications as are made obvious by those skilled in the art and guided by the teachings herein are intended to be within the scope of the invention as claimed.
A eutectic compound of dapagliflozin and glycine is a new crystal form formed by co-crystallizing dapagliflozin and glycine.
The fourier transform infrared absorption spectrum (FTIR) of the new crystal form of dapagliflozin (new eutectic) is shown in fig. 2 a.
The XRD pattern of the new dapagliflozin crystal form is shown in figure 3 a.
A pharmaceutical preparation comprises the novel dapagliflozin crystal form and can further comprise a pharmaceutically acceptable excipient.
The above pharmaceutical formulation is completed by dry granulation.
The above medicinal preparation is in the form of tablet, capsule, pill, powder or solution.
Such excipients include diluents, binders, disintegrants, lubricants, glidants, stabilizers, surfactants, dissolution enhancers, coloring agents, flavoring agents or mixtures thereof. The specific substances of each excipient are as described in the claims.
Examples
1. Preparation of novel dapagliflozin crystal form
For industrial production, the new crystal form can be prepared by a dry-process roll granulation process, which is a process without using any water or organic solvent, and which can improve productivity, simplify production process, and enable continuous production.
The rolling granulation process comprises the following steps:
1) conveying the raw materials to a compression area between the press wheels through a feeding system;
2) the compression device applies pressure to compact the raw material powder into a belt shape between two rollers rotating in opposite directions;
3) the granulation apparatus grinds the rolled strip to reduce its size and obtain a granular product of a specific size.
The preparation method adopts an industrialized rolling granulation process.
In the laboratory, the following methods can be used instead:
in this example, samples of dapagliflozin-glycine eutectic powder were made using a solid state milling process in which pure dry milling was used.
The new crystals were obtained by fine grinding by combining dapagliflozin base and glycine in dry solid form and applying pressure by hand (using a mortar and pestle) and ensuring that the temperature did not exceed 40 ℃.
In this example, dapagliflozin base was used as dapagliflozin monohydrate, available from moex corporation, minoua pharmaceuticals, inc. Of course, dapagliflozin monohydrate above is only a specific one of the dapagliflozin bases.
2. Other raw materials
As a comparative crystalline form, we chose dapagliflozin monohydrate.
FIG. 5a is an optical microscopic image of the comparative crystal form and FIG. 5b is an optical microscopic image of the novel crystal form of the present invention, from which it can be seen that the comparative crystal form is in the form of sharp needles as a whole, which adversely affects its flowability and suitability for subsequent processing; the novel crystal form of the present invention has a relatively rounder structure, thereby providing good flowability and processability.
Wherein, fig. 5a, 5b are optical microscope images obtained by taking two kinds of crystals, respectively, to be dispersed in a test tube containing paraffin oil, then mixing the dispersion for 2 to 3 minutes by a vortex mixing device and observing under an optical microscope 20X.
In addition, in each of FIGS. 2a-d and 3a-d, we provide FTIR patterns and XRD patterns.
From this we have found that the novel crystalline forms of dapagliflozin-glycine of the present invention do not have characteristic peaks for dapagliflozin and glycine; no new characteristic peaks were observed in XRD of the new crystals, but band changes of new wavelengths were seen in the infrared spectrum. Also, the percent mass loss with respect to temperature (i.e., weight loss curve) in the new crystals was also changed compared to dapagliflozin and glycine alone.
Thus, it is demonstrated that the new crystal form of dapagliflozin (or referred to as new crystal) prepared by the present invention is not a mixture but a new crystal.
3. Prescription preparation
3.1 prescription
Table 1 prescription composition ratio
(dapagliflozin propylene glycol monohydrate preparation VS dapagliflozin glycine co-crystal preparation)
Wherein the information of each raw material is as follows:
dapagliflozin propylene glycol monohydrate (comparative crystal form), specification D90: < 40um, source: xuancheng Meinuohua pharmaceutical Co., Ltd;
anhydrous lactose, size/model Supertab 22AN, source: DMV-Fonterra Excipients GmbH & Co.KG;
microcrystalline cellulose, size/model Avicel PH-302, source: future Mobility Corporation Ltd;
crospovidone, size/model Polyplasdon XL, source: ISP CHEMICALS LLC AFFILIATE OF ASHLAND;
colloidal silica, size/model AEROSIL 200Pharma, source: evonik Resource efficiency GmbH;
magnesium stearate, gauge/model Ligamed MF-2V, source: shanghai shipping Macro chemical preparations adjuvant technology Co., Ltd;
film coating premix (gastric soluble type), specification/model number opadry 85F92209-CN, source: shanghai Kalekang coating technology, Inc.
3.2 preparation process of the preparation:
1. sieving colloidal silicon dioxide (No. 2) and microcrystal (No. 3), mixing with dapagliflozin (No. 1a) or (No. 1b), and sieving with 40 mesh sieve;
2. putting the material obtained in the step-1 into a stirrer, and uniformly stirring for 15 minutes and 20 minutes;
3. sieving microcrystalline cellulose (No. 4), anhydrous lactose (No. 5), crospovidone (No. 6) and colloidal silicon dioxide (No. 7) with 40 mesh sieve;
4. putting the material obtained in the step-3 and the material obtained in the step-2 into a stirrer, stirring at the speed of 15 revolutions per minute for 20 minutes, and then unloading into a plastic bag;
5. the material from step-4 is fed at a suitable rate to a granulator equipped with KA099R
6. Sieving microcrystalline cellulose (No. 9) with 40 mesh sieve
7. The mixer and the blender were rinsed with microcrystalline cellulose (number 9) and collected in a plastic bag
8. Sieving magnesium stearate (No. 8) with 60 mesh sieve
9. Charging the materials of step 5 and step-6 into a blender, stirring at 12rpm for 3 minutes, and carefully collecting into plastic bags
10. Dry granulating the mixture of the materials obtained in the step 7
11. Measuring density and thickness of thin sheets
12. The flakes were crushed at medium speed using a 2.0 mm screen crusher and then crushed again at 1.0 mm.
13. The ground particles were collected in a plastic bag.
14. The percent yield was determined.
15. The amounts of added microcrystalline cellulose, crospovidone, silicon dioxide and magnesium stearate were calculated based on the calculated% yield.
16. Sieving colloidal silicon dioxide (No. 10), crospovidone (No. 11) and microcrystalline cellulose (No. 12) together with 40 mesh sieve, and sieving magnesium stearate (No. 13) with 60 mesh sieve
17. Charging the materials of the step-13 and the step-16 into a stirrer, and uniformly stirring at the speed of 15rpm for 15 minutes
18. The magnesium stearate from step-16 is charged into the blender along with the material from step-17 and mixed appropriately at 12rpm for 3 minutes
19. And detecting the bulk density, the tap density and the particle size distribution.
20. Tablets were compressed using 10.9 x 7.9 elliptical punches with a punch pressure in the hardness range of 90-110N.
21. Parameters during the process, such as disintegration time, friability, hardness, thickness and weight, were recorded.
22. The tablets were coated with opadry yellow-85F 92209-CN, with a 4% coating weight gain.
23. Medium temperature coating is used instead of high temperature coating.
3.3 prescription evaluation
The flowability of the active ingredient crystalline dapagliflozin propylene glycol monohydrate with the new crystals can be evaluated by the karl index and the hausner ratio.
Karl index equation:
carr index ═ tap density-bulk density/tap density × 100
Wherein, the unit of tap density: kg/m3(ii) a Unit of bulk density: kg/m3。
Hausner ratio equation:
hausner ratio ═ tap density/bulk density
Wherein, the unit of tap density: kg/m3(ii) a Unit of bulk density: kg/m3。
In addition, the hausner ratio can also be converted using the following equation:
haosner ratio H100/(100-Carl index)
Table 2 fluidity evaluation table
| Fluidity of the resin | Haosner ratio | Karl index |
| The fluidity is very good | 1.00～1.11 | ＜10 |
| Good fluidity | 1.12～1.18 | 11～15 |
| Normal fluidity | 1.19～1.25 | 16～20 |
| Has good fluidity | 1.26～1.34 | 21～25 |
| Poor fluidity | 1.35～1.45 | 26～31 |
| Very poor flowability | 1.46～1.59 | 32～37 |
| Almost no fluidity | ＞1.60 | ＞38 |
The hausner ratio and karr index determination flowability results for dapagliflozin propylene glycol monohydrate and dapagliflozin-glycine new co-crystal are as follows:
TABLE 3 Hausner ratio and Carr index determination of flowability results
The fluidity of the API is a key quality attribute (CQA) that affects the overall quality of the product.
| Serial number | The key quality genusProperty of (2) | Influence of | Remarks for |
| 1 | API flowability | Content uniformity | The results are as follows |
| 2 | Eutectic fluidity | Content uniformity | The results are as follows |
According to NMPA regulatory specifications, the acceptance criterion is less than 15.
And (4) conclusion:
the results refer to the original research manufacturer AstraZeneca at its evaluation report number: the use of crystalline dapagliflozin propylene glycol monohydrate is stated to have poor flowability, cohesion and stickiness, which may result in a low profile and concentration of dapagliflozin in a homogeneous premix being critical to achieving reproducible tablet content uniformity. Because this is done to control the blood glucose level of the patient, tablet non-uniformity can affect the patient and cause risks. This formulation will result in sub-therapeutic efficacy in the patient.
Further:
we determined that the root cause was due to poor API flowability and ultimately affected the overall quality of the product, as shown in the table above. Our research has found solutions, as well as all prior art solutions, where the flowability of the API is significantly increased and finally a good quality of the product is obtained. The use of the new co-crystal improves the product quality and robustness of the process.
Claims (10)
1. A co-crystal of dapagliflozin and glycine.
2. The eutectic of dapagliflozin and glycine according to claim 1, wherein an FTIR characteristic peak of the eutectic is 3171cm-1、2361cm-1And 1012cm-1。
3. The co-crystal of dapagliflozin and glycine according to claim 1, wherein the FRIT diagram of the co-crystal is shown in fig. 2 b; alternatively, the XRD pattern of the co-crystal is shown in fig. 3 b.
4. A pharmaceutical formulation comprising the co-crystal of dapagliflozin and glycine according to any one of claims 1 to 3.
5. The pharmaceutical formulation of claim 4, further comprising a pharmaceutically acceptable excipient.
6. The pharmaceutical formulation of claim 4, wherein the pharmaceutical formulation is completed by dry granulation.
7. The pharmaceutical formulation of claim 4, wherein the pharmaceutical formulation is in the form of a tablet, capsule, pill, powder, or solution.
8. The pharmaceutical formulation of claim 5, wherein the excipient comprises a diluent, a binder, a disintegrant, a lubricant, a glidant, a stabilizer, a surfactant, a dissolution enhancer, a coloring agent, a flavoring agent, or a mixture thereof.
9. The pharmaceutical formulation of claim 8, wherein the diluent is selected from the group consisting of: anhydrous lactose, lactose monohydrate, microcrystalline cellulose, co-processed microcrystalline cellulose and powdered cellulose, pregelatinized starch, corn starch, rice starch, potato starch and wheat starch, mannitol, sorbitol, xylitol and erythritol, calcium carbonate, calcium phosphate, calcium sulfate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate and tricalcium phosphate, and mixtures thereof;
the binder is selected from the group consisting of povidone, copovidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, gum arabic, tragacanth gum, sorbitol, glucose, sucrose, lactose, mannitol, gelatin, pullulan, sodium alginate, propylene glycol, polyvinyl alcohol, corn starch, modified corn starch, pregelatinized starch, methacrylate esters, carboxyvinyl polymers, waxes, and mixtures thereof;
the disintegrant is selected from the group consisting of croscarmellose sodium, hydroxypropyl cellulose, crospovidone, low substituted hydroxypropyl cellulose, microcrystalline cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, gums, alginic acid or alginates, starch, corn starch, pregelatinized starch, modified starch, sodium starch glycolate, carboxymethyl starch, polyacrylates, and mixtures thereof;
the lubricant is selected from stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, polyethylene glycol, talc, hydrogenated vegetable oils, fatty acids, waxes and mixtures thereof;
the glidant is selected from talc, silicon dioxide, colloidal anhydrous silicon dioxide, calcium silicate, magnesium silicate, hydrated silicon dioxide and mixtures thereof;
the stabilizer is selected from: hydroxypropyl methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose phthalate, sodium and calcium carboxymethylcellulose, polyvinylpyrrolidone, copovidone and polyvinyl alcohol, polyethylene glycol, block copolymers of ethylene oxide and/or propylene oxide, xanthan gum, gum arabic and/or derivatives thereof, pectin, alginates, acacia, gum tragacanth and/or derivatives thereof, carrageenan, agar and/or derivatives thereof, polysaccharides from microbial origin, starch, arabinogalactans, galactomannans, glucans, and mixtures thereof;
the surfactant is selected from sodium lauryl sulfate, sodium dodecyl sulfate, ammonium lauryl sulfate, benzalkonium chloride, ethylene oxide, copolymer of poly (ethylene oxide) and poly (propylene oxide), polyvinyl alcohol, fatty alcohol, polyoxyethylene alkyl ether, polyoxyethylene alkylaryl ether, polyethylene glycol fatty acid ester, alkylene glycol fatty acid monoester, sucrose fatty acid ester, sorbitan fatty acid monoester, and sorbitol monolaurate: (A), (B, C
20 or
80) Polyoxyethylene sorbitan fatty acid esters (polysorbates), and mixtures thereof;
the solubilizing agent is selected from the group consisting of sodium lauryl sulfate, polyethylene glycol, propylene glycol, glycerol monostearate, glycerol behenate, triglycerides, monohydric alcohols, higher alcohols, dimethyl sulfoxide, dimethylformamide, N-dimethylacetamide, N-methyl-2-pyrrolidone, N- (2-hydroxyethyl) pyrrolidone, 2-pyrrolidone, and mixtures thereof.
10. A method of treating a condition mediated by sodium-dependent glucose transporter (SGLT2), comprising administering to a subject in need thereof an effective amount of the dapagliflozin glycine co-crystal according to any one of claims 1-3, or comprising a pharmaceutical formulation according to claims 4-9, to achieve such treatment;
wherein the condition mediated by SGLT2 is type 2 diabetes;
wherein the subject is a human.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111552021.0A CN114085203A (en) | 2021-12-17 | 2021-12-17 | Dapagliflozin composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111552021.0A CN114085203A (en) | 2021-12-17 | 2021-12-17 | Dapagliflozin composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114085203A true CN114085203A (en) | 2022-02-25 |
Family
ID=80307552
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111552021.0A Pending CN114085203A (en) | 2021-12-17 | 2021-12-17 | Dapagliflozin composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114085203A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140343010A1 (en) * | 2013-04-29 | 2014-11-20 | Mapi Pharma Ltd. | Co-crystals of dapagliflozin |
| CN105524033A (en) * | 2014-09-28 | 2016-04-27 | 上海阳帆医药科技有限公司 | Fumaric acid eutectic of dapagliflozin, and preparation method and pharmaceutical composition thereof |
| US20170056365A1 (en) * | 2014-02-28 | 2017-03-02 | Sun Pharmaceutical Industries Limited | Dapagliflozin compositions |
| US20180362514A1 (en) * | 2015-09-15 | 2018-12-20 | Laurus Labs Ltd. | Co-crystals of sglt2 inhibitors, process for their preparation and pharmaceutical compositions thereof |
| CN110922372A (en) * | 2019-11-04 | 2020-03-27 | 天津大学 | Amino acid eutectic compound of dapagliflozin and preparation method thereof |
| WO2021023811A1 (en) * | 2019-08-07 | 2021-02-11 | Novo Nordisk A/S | Solid compositions comprising a glp-1 agonist, an sglt2 inhibitor and a salt of n-(8-(2-hydroxybenzoyl)amino)caprylic acid |
-
2021
- 2021-12-17 CN CN202111552021.0A patent/CN114085203A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140343010A1 (en) * | 2013-04-29 | 2014-11-20 | Mapi Pharma Ltd. | Co-crystals of dapagliflozin |
| US20170056365A1 (en) * | 2014-02-28 | 2017-03-02 | Sun Pharmaceutical Industries Limited | Dapagliflozin compositions |
| CN105524033A (en) * | 2014-09-28 | 2016-04-27 | 上海阳帆医药科技有限公司 | Fumaric acid eutectic of dapagliflozin, and preparation method and pharmaceutical composition thereof |
| US20180362514A1 (en) * | 2015-09-15 | 2018-12-20 | Laurus Labs Ltd. | Co-crystals of sglt2 inhibitors, process for their preparation and pharmaceutical compositions thereof |
| WO2021023811A1 (en) * | 2019-08-07 | 2021-02-11 | Novo Nordisk A/S | Solid compositions comprising a glp-1 agonist, an sglt2 inhibitor and a salt of n-(8-(2-hydroxybenzoyl)amino)caprylic acid |
| CN110922372A (en) * | 2019-11-04 | 2020-03-27 | 天津大学 | Amino acid eutectic compound of dapagliflozin and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20050043375A1 (en) | Solid preparation containing single crystal form | |
| EP2694110B2 (en) | Novel polysaccharide derivatives and dosage forms | |
| EP3852730A1 (en) | Pharmaceutical compositions of empagliflozin | |
| WO2017108605A1 (en) | Pharmaceutical composition comprising amorphous dasatinib | |
| EP1843754A1 (en) | New pharmaceutical composition containing candesartan cilexetil as lipophilic crystalline substance | |
| WO2011160541A1 (en) | Tolvaptan solid dispersion and its preparation method | |
| CN101721410B (en) | Solid medicinal composition of clopidogrel hydrogen sulfate | |
| CN103705478B (en) | Oral tablet containing tenofovir disoproxil fumarate | |
| CA2851862C (en) | Solid dosage forms of (s)-ethyl 2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate | |
| CA2934832C (en) | Solid preparations containing tofogliflozin and process of producing the same | |
| CN105434386B (en) | A kind of sustained-release tablet containing highly-water-soluble active constituent and preparation method thereof | |
| EP2694036A1 (en) | Pharmaceutical composition comprising fesoterodine | |
| US20120164227A1 (en) | New granulating process and thus prepared granulate | |
| EP2508175A1 (en) | Pharmaceutical composition comprising fesoterodine or a salt or a solvate thereof | |
| SG190025A1 (en) | A composition comprising s-[2-([[1-(2-ethylbutyl)-cyclohexyl]-carbonyl]amino)phenyl]2-methylpropanethioate and croscarmellose sodium | |
| CN105358137A (en) | Sovaprevir tablets | |
| CN114085203A (en) | Dapagliflozin composition | |
| EP2696857A1 (en) | Pharmaceutical composition comprising bosentan | |
| US20220226249A1 (en) | Solid tablet dosage form of ridinilazole | |
| IL111596A (en) | Process for preparing a clodronate preparation and pharmaceutical compositions containing it | |
| WO2017093890A1 (en) | Clobazam tablet formulation and process for its preparation | |
| JP2004352633A (en) | Magnesium oxide tablet | |
| EP3079672B1 (en) | Pharmaceutical composition comprising a pharmaceutically acceptable salt of rasagiline | |
| CN109700778B (en) | Cinacalcet hydrochloride quick-release preparation and preparation method thereof | |
| EP3928771A1 (en) | Pharmaceutical compositions of 1,2-benzisoxazole-3-methanesulfonamide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |