EP1606290A1 - Sels de faible basicite - Google Patents

Sels de faible basicite

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Publication number
EP1606290A1
EP1606290A1 EP04720454A EP04720454A EP1606290A1 EP 1606290 A1 EP1606290 A1 EP 1606290A1 EP 04720454 A EP04720454 A EP 04720454A EP 04720454 A EP04720454 A EP 04720454A EP 1606290 A1 EP1606290 A1 EP 1606290A1
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EP
European Patent Office
Prior art keywords
salt
pharmaceutical composition
carbendazim
carbon atoms
less
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.)
Withdrawn
Application number
EP04720454A
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German (de)
English (en)
Inventor
Samuel H. Yalkowsky
Tapan Sanghvi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Arizona Board of Regents of University of Arizona
University of Arizona
Original Assignee
Arizona Board of Regents of University of Arizona
University of Arizona
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Priority claimed from US10/402,347 external-priority patent/US7022712B2/en
Application filed by Arizona Board of Regents of University of Arizona, University of Arizona filed Critical Arizona Board of Regents of University of Arizona
Publication of EP1606290A1 publication Critical patent/EP1606290A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline

Definitions

  • This invention is in the field of improving the water solubility of benzimidazole derivatives and other weak bases and providing pharmaceutical formulations of the same.
  • Benzimidazole derivatives are useful for inhibiting the growth of cancers, tumors and viruses in mammals, particularly in humans and warm-blooded animals (U.S. Patents 6,479,526; 5,880,144; 6,245,789; 5,767,138; 6,265,437).
  • Certain benzimidazole derivatives used in combination with other compounds have been reported to be useful as fungicides (U.S. Patents 3,954,993; 4,593,040; 5,756,500; 4,835,169; 4,980,346).
  • benzimidazole derivatives including carbendazim
  • carbendazim are poorly water soluble.
  • the projected oral dose of carbendazim for cancer treatment is up to several hundred mg per day which is far greater than its water solubility.
  • Other weak bases suffer from the same poor water solubility.
  • 0004 There is a need for improved formulations of benzimidazole derivatives and other weak bases.
  • X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 4; Y is hydrogen, chlorine, nitro, methyl, ethyl or oxychloro; R is hydrogen, alkylaminocarbonyl wherein the alkyl group has from 3 to 6 carbon atoms or an alkyl group having from 1 to 8 carbons, and R 2 is 4-thiazolyl, NHCOORi wherein R 1 is an aliphatic hydrocarbon of less than 7 carbon atoms, or an alkyl group of less than 7 carbon atoms.
  • the salt is preferably one or more selected from the group consisting of: chlorides, bromides, phosphates, sulfates, tosylates, benzoylates, nitrates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates and mesylates.
  • Each salt comprising a weak base cation and individual anions and all groups and subgroups of anions are particular embodiments of the invention.
  • compositions comprising a salt of a weak base compound of formula:
  • X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 4; Y is hydrogen, chlorine, nitro, methyl, ethyl or oxychloro; R is hydrogen, alkylaminocarbonyl wherein the alkyl group has from 3 to 6 carbon atoms or an alkyl group having from 1 to 8 carbons and R 2 is 4-thiazolyl, NHCOORi wherein R1 is aliphatic hydrocarbon of less than 7 carbon atoms, or an alkyl group of less than 7 carbon atoms; one or more free acids; and optional pharmaceutical additives.
  • the salt and free acids are present in the composition at a ratio of about 1 :0.5 to about 1 :3 by weight. All individual values and ranges of ratios are included herein, including about 1 :1 and about 1 :2. Also provided are methods of making and using the salts and compositions described herein. Compositions consisting essentially of the components described herein are also included.
  • Also provided are methods of treating disease comprising administering to a patient a pharmaceutically effective amount of a pharmaceutical composition comprising a salt of a weak base compound of formula:
  • X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 4; Y is hydrogen, chlorine, nitro, methyl, ethyl or oxychloro; R is hydrogen, alkylaminocarbonyl wherein the alkyl group has from 3 to 6 carbon atoms or an alkyl group having from 1 to 8 carbons and R 2 is 4-thiazolyl, NHCOORi wherein R 1 is aliphatic hydrocarbon of less than 7 carbon atoms, or an alkyl group of less than 7 carbon atoms; one or more free acids; and optional pharmaceutical additives.
  • the salt and free acid are present in the composition at a ratio of about 1 :0.5 to about 1 :3 by weight. Other ratios as described herein are also included.
  • free acid means a composition that ionizes in water to form hydrogen ion and an anion.
  • the free acid contains the same anion as the salt.
  • the free acid contains one or more anions, one of which can be the same anion as in the salt.
  • salt means a composition that ionizes in water to form antician __ ⁇
  • the weak base provides the cation in the salt.
  • weak base or “weak bases” are those compounds having a pKa below about 7.
  • Weak bases include prodrugs of weak bases.
  • Preferred weak bases have a pKa below about 5.
  • Other preferred weak bases have a pKa below about 4.
  • Weak bases having pKa values below about 7 and compounds in all pKa ranges below about 7 are included in the invention.
  • Some classes of weak bases include: imidazole derivatives having a pKa below about 7, pyridine derivatives having a pKa below about 7, aniline derivatives having a pKa below about 7 and compounds containing combinations thereof having a pKa below about 7.
  • Imidazole derivatives are defined as compounds which include the structure:
  • Some preferred imidazole derivatives include the following:
  • Pyridine derivatives are defined as compounds which include the structure:
  • Some preferred pyridine derivatives include the following:
  • Aniline derivatives are defined as compounds which include the structure:
  • R is hydrogen or alkyl having from 1 to 7 carbon atoms.
  • the aromatic ring may have other substituents, as known in the art.
  • Some preferred aniline derivatives include the following:
  • One class of imidazole derivatives include those with the formula:
  • R is hydrogen, alkyl having from 1 to 7 carbon atoms, chloro, bromo, fluoro, oxychloro, hydroxy, sulfhydryl, or alkoxy having the formula -O(CH 2 ) y (CH3), wherein y is an integer from 0 to 6.
  • PG 300995 One particular compound of this class is PG 300995:
  • benzimidazoles are those having the formula:
  • X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms; n is a positive integer of less than 4; Y is hydrogen, chlorine, nitro, methyl, ethyl or oxychloro; R is hydrogen, alkylaminocarbonyl wherein the alkyl group has from 3 to 6 carbon atoms or an alkyl group having from 1 to 8 carbons and R 2 is 4-thiazolyl, NHCOORi wherein Ri is aliphatic hydrocarbon of less than 7 carbon atoms, or an alkyl group of less than 7 carbon atoms.
  • a preferred class of benzimidazoles are those wherein R is hydrogen. Another preferred class of benzimidazoles are:
  • R is an alkyl of 1 through 8 carbon atoms and R 2 is selected from the group consisting of 4-thiazolyl or NHCOORi wherein R is methyl, ethyl or isopropyl and pharmaceutically acceptable acid salts thereof with both organic and inorganic acids.
  • benzimidazole derivatives include benzimidazoles as defined above, and prodrugs of benzimidazoles.
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug (weak base) according to the formula of the parent drug described above in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of the weak bases are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate, or benzoate derivatives of alcohol and amine functional groups in the weak bases; phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carboxyalkyl esters of alcohol and phenol functional groups in the weak bases; and the like.
  • compositions of the invention are useful for administration to animals, preferably mammals, and preferably humans.
  • the compositions of the invention are administered using any form of administration and any suitable dosage that provides a pharmaceutically active dose in an animal, preferably a mammal, as known in the art.
  • compositions of the invention are used for oral, slow intravenous injection or infusion administration, as known in the art. Because the compositions are acidic, other forms of administration may be unsuitable. If the compositions are injected, the injection speed should be slow to avoid local irritation, as known in the art.
  • compositions of the invention may be formulated as known in the art, and described in WO 01/12169, U.S. 3,903,297, and U.S. 6,423,734 for example, all of which are incorporated by reference to the extent not inconsistent with the disclosure herewith, and especially for details of formulations.
  • compositions of the present invention may be administered in a unit dosage form and may be prepared by any method well known in the art without undue experimentation. Such methods include combining the compositions of the present invention with a carrier or diluent which constitutes one or more pharmaceutically acceptable additives, as known in the art without undue experimentation. Dosages of the compositions of the invention and frequency of adminstration are easily determined by means known in the art without undue experimentation.
  • Oral formulations suitable for use in the practice of the present invention include capsules, gels, cachets, tablets, effervescent or non-effervescent powders or tablets, powders or granules; as a solution or suspension in aqueous or non- aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion.
  • the compositions of the present invention may also be presented as a bolus, electuary or paste.
  • Capsules or tablets can include suitable additives that provide desired properties, such as binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and melting agents, as known in the art.
  • kits useful in treating disease which comprise one or more compositions of the invention and may include instructions for administration.
  • “Pharmaceutically acceptable” and “non-toxic” mean suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation and allergic response) commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically active” means capable of causing an intended physiological change in an animal, preferably a mammal.
  • “Pharmaceutically acceptable additives” include cosolvents, surfactants, complexants, hydrotropes and other components that are desired for pharmaceutical use, as known in the art, such as pharmaceutically acceptable carriers, preservatives, emulsifying agents, diluents, sweeteners, flavorants, viscosity controlling agents, thickeners, colorants and melting agents. Any level of pharmaceutically acceptable additives and any individual pharmaceutically acceptable additive or combination of additives may be used, as long as these additives do not reduce the solubility below a desired level or make the composition toxic, as defined above.
  • pharmaceutically acceptable carrier is known in the art, see, for example, U.S. Patent 6,479,526.
  • patient means an animal, mammal or human.
  • One class of patients is mammals.
  • One class of patients is human.
  • Figure 1 shows microscopic pictures of different salts of carbendazim.
  • Figure 2 shows x-ray powder patterns for different salts of carbendazim.
  • Figure 3 shows DSC thermograms of different salts of carbendazim.
  • Figure 4 shows HSM photographs of carbendazim sulfate.
  • Figure 5 shows TGA thermograms of carbendazim sulfate and carbendazim hydrochloride.
  • Figure 6 shows packing arrangement of sulfate salt along b-axis.
  • Figure 7 shows TGA thermograms of carbendazim hydrochloride at different heating rates.
  • Figure 9 shows thermal ellipsoid plot of molecules of different salts of carbendazim in the asymmetric unit at 50% probability, showing atomic numbering scheme: (a) hydrochloride; (b) phosphate; (c) sulfate; (d) mesylate; (e) besylate; and (f) tosylate.
  • Figure 10 shows helix type arrangement around a two fold screw axis; a: carbendazim moieties; b: hydrochloride salt.
  • Figure 11 shows packing arrangement of the phosphate salt along c-axis.
  • Figure 12 shows packing arrangement of the sulfate salt along b-axis.
  • Figure 13 shows packing arrangement of mesylate salt along b-axis.
  • Figure 14 shows packing arrangement of besylate salt along b-axis.
  • Figure 15 shows packing arrangement of tosylate against a two fold axis along c-axis.
  • Figure 16 shows moisture adsorption curves for different salts of carbendazim:
  • D hydrochloride salt
  • x sulfate salt
  • 0 tosylate salt
  • * besylate salt
  • A phosphate salt
  • ⁇ mesylate salt
  • Figure 17 shows powder x-ray diffraction patters for: (a) mesylate salt and (b) phosphate salt.
  • Figure 18 shows dissolution profiles of carbendazim and its salts in (a) water and (b) 0.1 N HCI; o: free base; 0: hydrochloride salt; x: phosphate salt, B:sulfate salt, ⁇ : mesylate salt; D: besylate salt; and A : tosylate salt.
  • Figure 19 shows dissolution profiles of phosphates in water; o: free base, *: physical mixture (1 :1), x: phosphate salt, and ⁇ : physical mixture (1 :2).
  • Figure 20 shows dissolution profiles of tosylates in water; ⁇ : tosylate salt, ⁇ : equimolar physical mixture of tosylate salt - p-toluenesulfonic acid.
  • Weak bases including benzimidazole derivatives are commercially available or can be prepared in a number of ways well known to one skilled in the art of organic synthesis without undue experimentation.
  • the benzimidazole derivatives are synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art without undue experimentation.
  • Benzimidazole derivatives may be prepared according to the method described in U.S. Pat. No. 3,738,995 issued to Adams et al, Jun. 12, 1973.
  • the thiazolyl derivatives may be prepared according to the method described in Brown et al., J. Am. Chem. Soc, 83 1764 (1961) and Grenda et al., J. Org. Chem., 30, 259 (1965).
  • Carbendazim was provided by the Procter & Gamble Company (Cincinnati,
  • the major issue for salt selection of an ionizable drug is the consideration of the relative basicity (or acidity) of the drug and the relative strength of the conjugate acid (base).
  • the pK a of the conjugate acid has to be at least two units less than the pK a of the basic centre of the drug.
  • the selected counter-ion should possess minimal toxic effects.
  • Carbendazim has basic pK a of 4.5.
  • anionic counter-ions were used for salt preparation:
  • Phosphoric acid (0.98 g) was added to 100 ml of water kept on a heating plate maintained at 70°C. To this solution, 1.92 g of carbendazim was then added portionwise. On reacting to form the salt, carbendazim started dissolving. The system was heated to favor the reaction and to increase the solubility of the formed salt. The slurry was constantly stirred at 250 rpm for about 60 min until a saturated solution was obtained. The saturated solution was vacuum filtered immediately using a preheated (70°C) glass filter into a conical flask that was preequilibrated at (70°C).
  • the final filterate was cooled slowly to room temperature by putting it back on the heating plate programmed to 2°C/min decrease in temperature.
  • the solution was then left at room temperature for overnight, whereby needle shaped crystals crashed out of the solution.
  • the formed crystals were removed from the water using a spatula and dried on filter paper to ensure evaporation of surface water molecules.
  • DSC thermogravimetric analysis
  • TGA thermogravimetric analysis
  • HSM hot stage microscopy
  • the PXRD patterns of different salts of carbendazim were determined at ambient temperature and atmosphere using a Philips PM 990/100 diffractometer (Philips, The Netherlands).
  • the x-ray generator (PW3373/00 Cu LFF DK119706) has a copper radiation source which generates a voltage of 50 kV, and a current of 40 mA.
  • Counts were measured using a X'Celerator detector which is based on real time multiple strip (RTMS) technology. Samples were packed into zero background silicon sample holders, and precautions were used to avoid introducing preferred orientation of the crystallites. The samples were subjected to a spinning movement having a rotation time of 4 s.
  • the samples were scanned with the diffraction angle, 20, increasing from 3° to 63°, with a step size of 0.0167° and a counting time of 15.24 s.
  • the XRD pattern traces of samples were compared with regard to peak position and relative intensity, peak shifting, and the presence or lack of peaks in certain angular regions.
  • the filterate was collected in two or more fractions, which were analyzed separately by HPLC to ensure that there were no misleading solubility measurements resulting from adsorption onto the filter. Filter adsorption was assumed to be negligible when the concentration of successive fractions agreed within ⁇ 5%.
  • the composition of the residual solid was examined to ensure that at least some of the solid phase that was in equilibrium with the solution was indeed the salt.
  • the solubility of the different salts was also determined in 0.01 M and 0.1 M of the corresponding acids.
  • K sp determinations were generally calculated directly from the observed carbendazim concentration once it was established that the residual solid phase contained excess salt. Since free acid precipitation results in the neutralization of an equivalent amount of counterion to its free base form, the same procedure could be used to calculate K sp in systems where free acid precipitation occurred prior to saturation of the system with the given salt.
  • Each of the prepared salts had a distinct characteristic PXRD pattern, as shown in Figure 2. These PXRD patterns were compared with the respective samples that were subjected to moisture sorption studies or stability studies. Table 2a. Crystallographic data for single x-ray crystal structure of different carbendazim salts
  • Hot stage microscopy was used to ascertain different thermal events that were shown in the DSC traces of the hydrochloride and the sulfate salt.
  • Figure 4 shows the sequence of events recorded while heating a sample of carbendazim sulfate.
  • the first endotherm (A) at 135°C in the DSC trace of the sulfate salt probably corresponds to the melt of the salt accompanied by dehydration of the hydrated salt.
  • the formation of air bubbles indicates liberation of water molecules, and shrinkage of molecules represents the melt.
  • the basis for this endotherm was further investigated by using TGA.
  • the TGA scan shown in Figure 5 indicates a weight loss of about 19% over the temperature range of 120 - 170°C.
  • the sulfate salt was heated in an oven maintained at 140°C, then the sample was run on the HPLC using the procedure previously described to check for the presence of carbendazim.
  • the eluent at 3.5 min had a uv spectra similar to the original compound, thereby validating the assumption.
  • recrystallization again occurs to form dendritic crystals.
  • This dendritic crystal continues to grow until it melts, indicated by the third endotherm on the DSC trace, which happens to be the degradation product.
  • the temperature of the first endotherm exceeds the boiling point of water by 35°C, which indicates formation of a stable ionic hydrate.
  • the guest water molecules in the sulfate salt are located in isolated cavities along the length of the b-axis, forming H-bonds with sulfate, carbendazim and other water molecules. Dehydration of the crystal must therefore involve complete disruption of the crystal structure, as shown in Figure 6, and should occur at a relatively high temperature owing to strong host-guest hydrogen bonding, and location of guest molecules in the isolated cavities.
  • the melting enthalpy of the higher melting form B is lower than the melting enthalpy of A. Therefore, the two forms are enantiotropically related, however only form A is stable below the transition temperature.
  • the hydrochloride salt was found to undergo dehydration at 66°C, followed by a melting endotherm at 120°C.
  • the weight loss of 13.1 % ( Figure 5) over the temperature range 45-86°C agrees with the theoretical value of 13.6%, which was calculated for a solvate containing two molecules of water for each molecule of the hydrochloride salt.
  • the hydrochloride salt was found to have three forms, which are also related enantiotropically.
  • This method involves the analysis of weight loss versus temperature at different heating rates ( ⁇ ) to determine the corresponding absolute temperatures at a constant weight loss (C).
  • Graphs of negative logarithm of heating rates (expressed in °C/s) (-log ⁇ ) versus 1/T were plotted ( Figure 8) and the activation energy calculated from the slope of the curves.
  • the carbendazim moiety in all the studied salts was found to be arranged planar, irrespective of the crystal system/space group, and/or the counter-ion present in the crystal lattice. This is not surprising, as the presence of a benzimidazole ring on one end makes the molecule as a whole planar. Interestingly, the carbonyl group next to the oxygen of methoxy group imparts a slight sp 2 character to the oxygen, thereby restricting the free rotation of the methoxy group. This is confirmed by the inability of the oxygen to form a hydrogen bond with any of the available H - donors. None of the salts demonstrated intra or intermolecular hydrogen bonding between the carbendazim molecules, except for the sulfate salt, wherein there existed a weak C-H...O intermolecular hydrogen bond.
  • the packing arrangement of organic salts is mainly determined by its ability to form inter and intramolecular hydrogen bonds, and to a lesser extent, by van der Waals interactions.
  • knowledge of hydrogen bond strength along with the hydrogen bond number (HBN) can be used in a qualitative fashion for correlations with melting point. It should be remembered that a compound's melting point is a function of several parameters, such as symmetry, eccentricity, packing, flexibity, and hydrogen bonding.
  • the strength of a hydrogen bond is a function of the electronegativity of the donor (D) and the acceptor (A) atoms. Since the closeness of the D and A atoms in a crystal is a measure of how effectively the hydrogen is acting as a mutual attractor, the crystallograghic A-B distances can be used as a measure of hydrogen bond strength.
  • HBN is defined as the maximum number of hydrogen bonds that can exist in a repeating lattice. It is equal to twice the minimum of either the number of bondable hydrogens or the number of hydrogen bond acceptor sites on the molecule.
  • the phosphate salt also forms reinforced hydrogen bonds between the phosphate moieties, however, the carbendazim molecule is only moderately bonded to the phosphate, and therefore has melting point less than sulfonates, but greater than both the hydrochloride and the sulfate.
  • both the hydrochloride and the sulfate salt form a number of H-bonds (at least six), which may compete with each other and limit the formation of all bonds. It is very likely that the geometric constraints imposed by some H-bonds may severely inhibit additional bonds, resulting in low melting points. Because of less stringent requirements, both the sulfate and the hydrochloride salts are closely packed.
  • incorporation of solvent molecules into the crystal lattice appears to be positively or negatively related to attaining the maximum hydrogen bond number.
  • the hydrochloride and sulfate salts are deficient in acceptor and donor atoms.
  • the use of water as the solvent in these lattices is analogous to sharing electrons, allowing the hydrochloride and the sulfate to attain stable crystal structures.
  • the hydrochloride salt of carbendazim is crystallized in the orthorhombic space group P2 1 2 ⁇ 2- t .
  • This space group is chiral, and does not have any symmetry operations associated with inversion or mirror. Thus, it is devoid of a centre of symmetry and aptly defined as non-centrosymmefric.
  • the symmetry operation for this space group involves both rotation and translation along a given axis, referred to as the screw axis.
  • three two-fold screw axes are present along the a, b, and c directions.
  • 2 ⁇ mean that the asymmetric unit moves 14 of a repeat unit along the three axes for each 14 of a revolution about that axis.
  • the asymmetric unit of the carbendazim hydrochloride salt contains one molecule each of hydrochloride and carbendazim, along with two water molecules. The presence of two water molecules in the unit pattern illustrates the importance of water during the crystallization process.
  • the thermal ellipsoidal diagram of the hydrochloride salt ( Figure 9(a)) includes the atomic labeling scheme, while the stereo packing diagram of its unit cell is shown in Figure 10.
  • the chloride anion along with the water molecules act as a cross linker for the carbendazim assemblies.
  • the self-assembly patterns of carbendazim molecules (present as cationic species) arrange themselves in infinite helices around a two-fold screw axis, connecting through ⁇ - ⁇ stacking involving imidazole and a phenyl ring ( Figure 10(a)).
  • Such assemblies create voids in which chloride ions and water molecules are contained (Figure 10(b)).
  • the chloride ions interact with the surrounding carbendazim ions and water molecules through multiple hydrogen bonds, one hydrogen bond with carbendazim (N(14)-H(14A)...CI(17)), and one hydrogen bond with each of the two water molecules (O(15)-H(15B)...CI(17) and O(16)-H(16A)...CI(17)).
  • the water molecules also form hydrogen bonds with nitrogen (N(5) and N(7)) and oxygen (O(4)) of carbendazim ion.
  • the two water molecules are also connected together through intermolecular hydrogen bonding.
  • a novel feature in the carbendazim hydrochloride assembly is the presence of
  • D and A refer to donor and acceptor atoms, respectively.
  • the phosphate salt of carbendazim crystallizes in the triclinic system, having centrosymmetric space group, P ⁇ .
  • the triclinic crystal systems have no restrictions regarding cell edges and cell angles.
  • the only symmetry operation for the P ⁇ space group is inversion through a point. Since this inversion is along a one-fold axis, it is equivalent to the centre of symmetry. Based on these symmetry operation, we can have two equipoint transformations (x,y,z and -x,-y,-z), yielding the general position multiplicity of 2 in the unit cell.
  • This salt adopts a specific molecular conformation, which promotes intermolecular hydrogen bonding.
  • this drug molecule is monoprotonated, with a 1 :1 molecular ratio between the drug molecule and the phosphate anion.
  • the three N-H donors (N(4), N(7), and N(14)) of the drug molecule and the oxygen acceptor of the phosphate anion participate in the hydrogen bonding.
  • the oxygen 0(12) and 0(14) act as acceptors, and each forms two H-bond interactions, one with the protonated drug and the other with the phosphate anion.
  • 0(13) acts both as an acceptor (N(7)-H(10A)...O(13)) and a donor (O(13)-H(13B)...O(12)) to form H-bond interactions.
  • 0(11) acts as a donor, forming intermolecular H-bonds with the 0(14) of the phosphate anion.
  • the strong intermolecular N-H...O bond between the NHs of the cationic drug moiety and the oxygen of the anionic phosphate serve to link neighboring carbendazim molecules into chains.
  • the O-H...O hydrogen bonds between the phosphate molecules allows the arrangement of the anion molecules into a line parallel to the b axis ( Figure 11).
  • D and A refer to donor and acceptor atoms, respectively.
  • the packing arrangement of phosphate salt shows that both carbendazim and phosphate anions are arranged in stacks of parallel molecules, while the molecules in adjacent stacks are arranged in an inverted fashion. Within the stacks, the molecules are all arranged in the same direction.
  • the most intense inter-molecular interactions in carbendazim occur among adjacent stacks between the carbon of the carbonyl group and the ⁇ system of the benzene ring.
  • the observed bond length (C(3)-C(10)) of 3.261 A is less than the van der Waals value of 3.4A.
  • the strong electron acceptor character of the carbonyl oxygen induces the formation of ⁇ - complexes.
  • Carbendazim sulfate crystallizes in the monoclinic system, having centrosymmetric space group C2/c.
  • monoclinic system there is a "unique" axis - the one which is perpendicular to the other two. This unique axis is normally chosen as the b-axis, and thus, ⁇ ⁇ 90°.
  • the crystal pattern for the sulfate salt is centered, unlike the hydrochloride or the phosphate salt that have primitive patterns. In a centered pattern, the grouping of motifs at the center of the rectangular cell is identical with that at the corners.
  • the symbol 'C indicates that the lattice is face- centered or end-centered, with a second lattice point lying at the center of the C-face (which is defined by the a- and b- axes).
  • the cell volume is double that of the primitive cell.
  • the symmetry operation is a 2-fold rotation axis parallel to the b-axis, and a glide plane perpendicular to the b-axis.
  • the symbol 'c' indicates that the direction of glide is parallel to the c-axis.
  • a glide plane combines the operation of reflection with that of translation, and therefore occurs only in extended arrays.
  • the asymmetric unit consists of a single protonated carbendazim molecule, one water molecule, and a half sulfate anion.
  • the sulfate salt adopts a molecular conformation which promotes intermolecular hydrogen bonding.
  • the three N-H donors of the drug molecule and the sulfate oxygen acceptor of the anion, along with the water molecule participate in hydrogen bonding.
  • Strong intermolecular hydrogen bonds between the NHs (both imidazole and carbamate) and the sulfate or water oxygens link the protonated carbendazim, the sulfate anions, and the water molecules into chains, which propogate along the b-axis ( Figure 12).
  • the packing diagram of this salt closely resembles that of the phosphate salt, having a column of anion, SO 4 2" in this case, running parallel to the b axis, where the sulfate molecules are hydrogen bonded to the water molecules (O(20)-H(21)...O(10) and O(20)- H(20)...O(11)).
  • the drug molecule is again H-bonded to the anion on each side of the molecule, just as they do in the phosphate salt (N(7)- H(7A)...O(10), N(5)- H(5A)...O(11), N(5)-H(5A)...S(1) and N(7)-H(7A)...S(1).
  • the drug molecule also forms hydrogen bonds with the water molecule (N(14)- H(14A)...O(20)).
  • D and A refer to donor and acceptor atoms, respectively.
  • the packing arrangement of the sulfate salt shows the presence of intermolecular hydrogen bonds having carbon as the hydrogen donor.
  • an activated C-H group as present in some heterocyclic bases, for example, caffeine, theophylline, uric acid and related compounds, tend to interact with oxygen atoms in the same way as an O-H or N-H group and the short ( ⁇ 3.4A) C--0 contacts observed in the crystals of these molecules were interpreted as C- H...O hydrogen bonds.
  • the packing arrangement of the sulfate salt is stabilized by the presence of C-H... ⁇ interactions between the methyl group of one carbendazim and the benzene ring of the other. These interactions are C(11)... H(1C) (2.797A) and C(10)... H(1C) (2.676A).
  • the carbendazim mesylate salt like the sulfate, crystallizes in a monoclinic system, although the mesylate salt has a different space group, Cc. Also, unlike other carbendazim sulfonate salts, the Bravais lattice for the mesylate salt is centered. The only symmetry operation associated with this space group is a glide plane in the direction parallel to the c-axis. This space group is chiral, having a z value of 4. The general positions are given by (x,y,z), (!4+x,14-y,z), (x,-y, 1 +z), and ( 1 / 2 +x, 1 / 2 -y, 1 / 2 +z).
  • the asymmetric unit consists of one molecule each of protonated carbendazim and anionic methane sulfonate.
  • a projection along the b-axis of the atomic arrangement of the salt is depicted in Figure 13.
  • the packing consists of alternate parallel stacks of protonated carbendazim and mesylate anions. These stacks are parallel to the a-axis ( Figure 13), and within each stack, all molecules are oriented in the same direction. These stacks of carbendazim and methanesulfonic acid are held together by intermolecular hydrogen bonds and C-H... ⁇ interactions.
  • D and A refer to donor and acceptor atoms, respectively.
  • the asymmetric unit consists of one molecule each of carbendazim and benzenesulfonic acid.
  • Carbendazim appears as a planar molecule in the asymmetric unit, with the benzenesulfonic acid perpendicular to it.
  • the packing arrangement of the salt shows the presence of intermolecular hydrogen bonding between the protonated carbendazim and the benzenesulfonate anion ( Figure 14). However, no intramolecular hydrogen bonding or intermolecular hydrogen bonding was observed between two carbendazim molecules or two benzenesulfonic acid molecules. As with the other salts, all hydrogen donating atoms (N) form hydrogen bonds with hydrogen acceptor atoms (O and S). Unlike the hydrochloride and sulfate salts, however, the packing motif of the besylate salt allows formation of two intermolecular hydrogen bonds involving carbon as the donor.
  • the phenyl carbons (C(22) and C(23)) of the benzenesulfonate anion forms hydrogen bonds with the methoxy oxygen (O(2)) of the carbendazim molecule.
  • the bond lengths (C--O) for both C-H...O bonds is less than 3.4A, and the bond angle is greater than 130°. Because of the intermolecular hydrogen bonds between carbendazim and benzenesulfonate anion, the carbendazim molecules are arranged along the b-axis.
  • D and A refer to donor and acceptor atoms, respectively.
  • the carbendazim tosylate salt crystallizes in the orthorhombic system having space group P2 ⁇ 2-
  • This space group does not have any symmetry operations associated with inversion or mirror, and thus is devoid of a centre of symmetry and aptly defined as non-centrosymmetric.
  • the symmetry operation for this space group involves both rotation and translation along a screw axis.
  • three two-fold screw axes are present along the a, b, and c directions.
  • 2 ⁇ 2 ⁇ 2 ⁇ mean that the asymmetric unit moves 14 of a repeat unit along the three axes for each 14 of a revolution about that axis.
  • the asymmetric unit consists of one molecule each of carbendazim and toluenesulfonic acid. As seen in figure 9(f), the carbendazim molecule and the toluenesulfonic acid lie perpendicular to each other.
  • the unit cell contains four molecules each of carbendazim and toluenesulfonic acid. The molecules are arranged in alternate layers of carbendazim and tosylate, in all three directions ( Figure 15).
  • the carbendazim and tosylate molecules in the tosylate salt are arranged in infinite helices around a two-fold screw axis.
  • the carbendazim molecules within the stacks are flipped by 180°, whereas the tosylate molecules are oriented in the same direction.
  • the molecules of adjacent stacks of carbendazim show an inclination angle of ⁇ 41.11 ° to the stack axis, which is the case a-axis in this case.
  • the packing arrangement of tosylate shows intermolecular hydrogen bonding (Table 11) between the NHs of carbendazim and Os and S of tosylate.
  • the packing arrangement for tosylate like besylate, shows a number of edge-to-face as well as CH- ⁇ interactions. These interactions are not only between the phenyl rings of carbendazim and p-toluenesulfonic acid but also between the methyl group of carbendazim and the phenyl ring of p-toluenesulfonic acid.
  • D and A refer to donor and acceptor atoms, respectively.
  • the packing efficiency can be interpreted by measuring the packing coefficient, K, for a given crystal.
  • the packing coefficient represents the amount of space filled by the molecules in a lattice, and is calculated as
  • a high degree of moisture sorption or desorption by the salts at 30-50% RH, the expected humidity conditions of pharmaceutical manufacturing plants may create numerous handling and manufacturing difficulties including change in the drug's potency and true density, variation in flow properties, dissolution rates and bioavailability, as well as chemical instability.
  • general trends have been noted between the propensities of salts to form hydrates and various structural features such as counter-ion radius and charge, a given salt may form several stoichiometric hydrates depending upon the crystallization conditions.
  • an assessment of a compound's ability to adsorb moisture is an important developability criterion.
  • FIG 16 shows the moisture adsorption curves for carbendazim salts under relative humidity values of 43 and 81 %.
  • the hydrochloride and sulfate salt were minimally hygroscopic, adsorbing less than 1% moisture at both 43 and 81 % RH.
  • both of these salts were synthesized as hydrates.
  • the phosphate and mesylate salts were found to be highly hygroscopic, adsorbing 7.5 and 10.1% moisture at 81 % RH compared to 1-2% at 43% RH.
  • the besylate and tosylate salts adsorbed less than 1 % moisture at 43% RH, and approximately 4.3% at 81% RH.
  • the aqueous solubilities of the hydrochloride, phosphate, sulfate, besylate, and tosylate salts of carbendazim at 25°C are listed in Table 13.
  • the mesylate salt was found to be highly soluble (> 200 mg/ml), and therefore its saturable solubility was not determined.
  • the solubility of sulfate reached a plateau at approximately 1.2 x 10 2 M in the region below pH 1.58, indicating that the solution is saturated with respect to sulfate salt below this pH.
  • the solubility of both besylate and the tosylate decreased below a pH value of 1.65 and 1.82, respectively.
  • the solubility products of the different salts are also tabulated in Table 13.
  • a salt exhibits a higher dissolution rate than the base at any given pH, despite having the same equilibrium solubilities. It is believed the salt effectively acts as its own “buffer” to alter the pH of the diffusion boundary layer, thereby increasing the apparent solubility of the parent drug within that layer.
  • administration of basic drugs in their salt forms ensures that stomach emptying, rather than in vivo dissolution, will be the rate-limiting factor in its absorption. From the dissolution studies it is evident that the formed salts have better dissolution than the free base. In water, mesylate dissolved the fastest.
  • solution not saturated with mesylate salt tto% and t 6 o% represents time for dissolution of 40% and 60% of given amount of salt/free base (equivalent to 50mg carbendazim)
  • Free acid in formulations comprising salts of weak base compounds described herein results in improved dissolution of the weak base compound.
  • the dissolution can be faster or more complete than in formulations not containing additional acid.
  • the ratio of salt of weak base to free acid can be any ratio, however about 1 :0.5 to about 1 :3 are particular useful ratios, including all intermediate values and ratios therein.
  • Particular examples of compositions include a phosphoric acid salt of a weak base combined with phosphoric acid free acid in the ratios described above.
  • Other particular examples of compositions of the invention include a chloride salt of a weak base combined with a hydrochloric acid free acid in the ratios described above.
  • compositions of the invention include a sulfate salt of a weak base combined with a sulfuric acid free acid in the ratios described above.
  • Other particular examples of compositions of the invention include a mesylate salt of a weak base combined with a methanesulfonic acid free acid in the ratios described above.
  • Other particular examples of compositions of the invention include a besylate salt of a weak base combined with a benzenesulfonic acid free acid in the ratios described above.
  • compositions of the invention include a tosylate salt of a weak base combined with a toluenesulfonic acid free acid in the ratios described above.
  • the free acid can be the same as the acid used to prepare the salt, or can be different.
  • the free acid can also be a mixture of the acid used to prepare the salt and one or more acids not used to prepare the salt.
  • One particular weak base useful in formulations is carbendazim.

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Abstract

L'invention concerne des compositions pharmaceutiques comprenant: un sel d'un composé de faible basicité de formule (I) dans laquelle X est hydrogène, halogène, alkyle comportant moins de 7 atomes de carbone ou alcoxy comportant moins de 7 atomes de carbone; n est un entier positif inférieur à 4; Y est hydrogène, chlore, nitro, méthyle, éthyle ou oxychloro; R est hydrogène, alkylaminocarbonyle dont le groupe alkyle présente 3 à 6 atomes de carbone ou un groupe alkyle présentant 1 à 8 atomes de carbone; et R2 est thiazolyle, NHCOOR1, dans lequel R est un hydrocarbure aliphatique présentant moins de 7 atomes de carbone ou un groupe alkyle présentant moins de 7 atomes de carbone; un ou plusieurs acides libres; et des additifs pharmaceutiques facultatifs.
EP04720454A 2003-03-12 2004-03-12 Sels de faible basicite Withdrawn EP1606290A1 (fr)

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US45403503P 2003-03-12 2003-03-12
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US454514P 2003-03-13
US10/402,347 US7022712B2 (en) 2002-03-26 2003-03-26 Solubilization of weak bases
US402347 2003-03-26
PCT/US2004/007786 WO2004081006A1 (fr) 2003-03-12 2004-03-12 Sels de faible basicite

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Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7407955B2 (en) 2002-08-21 2008-08-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US7501426B2 (en) 2004-02-18 2009-03-10 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
DE102004054054A1 (de) 2004-11-05 2006-05-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine
DE102005035891A1 (de) * 2005-07-30 2007-02-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel
PE20080251A1 (es) 2006-05-04 2008-04-25 Boehringer Ingelheim Int Usos de inhibidores de dpp iv
CN102838599A (zh) 2006-05-04 2012-12-26 贝林格尔.英格海姆国际有限公司 多晶型
EP1852108A1 (fr) 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG Compositions d'inhibiteurs de la DPP IV
AR071175A1 (es) 2008-04-03 2010-06-02 Boehringer Ingelheim Int Composicion farmaceutica que comprende un inhibidor de la dipeptidil-peptidasa-4 (dpp4) y un farmaco acompanante
KR20200118243A (ko) 2008-08-06 2020-10-14 베링거 인겔하임 인터내셔날 게엠베하 메트포르민 요법이 부적합한 환자에서의 당뇨병 치료
UY32030A (es) 2008-08-06 2010-03-26 Boehringer Ingelheim Int "tratamiento para diabetes en pacientes inapropiados para terapia con metformina"
CA2736421A1 (fr) 2008-09-10 2010-03-18 Boehringer Ingelheim International Gmbh Polytherapie pour le traitement du diabete et des etats pathologiques apparentes
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
CN103965204B (zh) * 2008-11-19 2016-09-07 赛福伦公司 吲唑并[5,4-a]吡咯并[3,4-c]咔唑化合物的新形式
JP2012512848A (ja) 2008-12-23 2012-06-07 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 有機化合物の塩の形態
AR074990A1 (es) 2009-01-07 2011-03-02 Boehringer Ingelheim Int Tratamiento de diabetes en pacientes con un control glucemico inadecuado a pesar de la terapia con metformina
JP2013512229A (ja) 2009-11-27 2013-04-11 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 遺伝子型が同定された糖尿病患者のリナグリプチン等のｄｄｐ−ｉｖ阻害薬による治療
KR101927068B1 (ko) 2010-05-05 2018-12-10 베링거 인겔하임 인터내셔날 게엠베하 체중 감소 치료에 후속하는 dpp-4 억제제에 의한 순차적 병용 요법
CN102971005A (zh) 2010-06-24 2013-03-13 贝林格尔.英格海姆国际有限公司 糖尿病治疗
AR083878A1 (es) 2010-11-15 2013-03-27 Boehringer Ingelheim Int Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento
JP5876150B2 (ja) 2011-07-15 2016-03-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 置換キナゾリン、これらの調製及び医薬組成物中のこれらの使用
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
WO2013171167A1 (fr) 2012-05-14 2013-11-21 Boehringer Ingelheim International Gmbh Dérivé de xanthine en tant qu'inhibiteur de dpp-4 pour l'utilisation dans le traitement de troubles associés aux podocytes et/ou un syndrome néphrotique
WO2013174767A1 (fr) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh Dérivé de xanthine en tant qu'inhibiteur de la dpp-4 à utiliser dans la modification de l'apport alimentaire et dans la régulation des préférences alimentaires
EP3110449B1 (fr) 2014-02-28 2023-06-28 Boehringer Ingelheim International GmbH Utilisation médicale d'un inhibiteur de dpp-4
AU2017276758A1 (en) 2016-06-10 2018-11-08 Boehringer Ingelheim International Gmbh Combinations of Linagliptin and metformin

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1195180A (en) * 1967-05-05 1970-06-17 Du Pont Use of Alkyl 2-Benzimidazole-Carbamate Salts a Fungicides
CA962588A (en) * 1972-05-17 1975-02-11 Her Majesty In Right Of Canada As Represented By The Minister Of The Env Ironment, And Canadian Patents And Development Limited Method, apparatus, and fungicides for the treatment of trees subject to dutch elm disease and other fungus diseases
JPS5459338A (en) * 1977-10-20 1979-05-12 Takeda Chem Ind Ltd Remedy for dermatomycosis
HU199431B (en) * 1985-02-04 1990-02-28 Chinoin Gyogyszer Es Vegyeszet Process for producing carbendazim salts, and fungicide comprising such carbendazim salt as active ingredient
US6423734B1 (en) * 1999-08-13 2002-07-23 The Procter & Gamble Company Method of preventing cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004081006A1 *

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