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Chemistry » Inorganic Chemistry » "Advanced Topics in Crystallization", book edited by Yitzhak Mastai , ISBN 978-953-51-2125-1, Published: May 6, 2015 under CC BY 3.0 license. © The Author(s).

Chapter 6

Role of Crystallization in Genesis of Diverse Crystal Forms of Antidiabetic Agents

By Renu Chadha, Dimpy Rani and Parnika Goyal
DOI: 10.5772/59674

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Role of Crystallization in Genesis of Diverse Crystal Forms of Antidiabetic Agents

Renu Chadha1, Dimpy Rani1 and Parnika Goyal1

1. Introduction

Crystallization is a crucial step in the manufacturing and processing of active pharmaceutical ingredients (API’s) in pharmaceutical industry [1]. As crystallization is coupled with molecular recognition, a slight alteration in crystallization conditions can affect crystal and powder properties accompanied with thermodynamic and mechanical properties [2]. So, the selection of an appropriate solid form of an active pharmaceutical ingredient (API) in the early stages of drug development is very important as it can be pure crystalline form or its non covalent modification such as polymorph, amorphate, hydrate, solvate, salt or co-crystals exhibiting unique physicochemical properties (solubility, dissolution rates, stability and bioavailability) and other performances characteristics of drug [3].

Existence of a crystalline solid into many crystalline forms leads to polymorphism which is a phenomenon, hard to predict. It may be of two types either conformational (due to existence of various conformers of molecule) or packing polymorphism (due to difference in crystal packing). On thermodynamic consideration, there are also two types of polymorphism i.e., monotropic system (when the transition of one form to another is irreversible) and enantiotropic system (reversible forms) [4]. In general, least stable crystal form crystallizes out first, not the most stable form. Metastable crystal form (unstable) tend to change to more stable from under particular conditions [5]. Crystal forms are the entities which are similar at molecular level but dissimilar in supramolecular aspect [6].

The various conditions used in the process of crystallization is the chief cause of generation of different crystal forms of a molecule and the difference in the properties of various crystal forms is due to different crystal packing and lattice energy [4]. Advancement in synthesis has gained control on the synthesis and purity of drugs but still lag behind in controlling the crystallinity and physical crystal forms. Different forms of a crystalline solid can be controlled by controlling the crystallization process.

The best method used for obtaining the variety of crystal forms is crystallization as it is traditional, easy and unbeatable process. Crystallization techniques may be solvent or non-solvent based and varied methods give rise to different forms. Solvent crystallization techniques include solvent evaporation, slow cooling of the solution, diffusion, vapour diffusion while non solvent techniques include sublimation, thermal treatment, desolvation of solvates, grinding and crystallization from melt etc. The choice of appropriate technique may be decided depending on the amount of sample and physical stability or solubility of drug [7-8].

Different crystal forms due to different crystal lattice have different physicochemical properties and thus therapeutic effects. Thus, Pharmaceutical companies usually search for a crystal form or polymorph with the best properties for therapeutic use and manufacturability. Selection of an optimized crystal form is of more relevance as regulatory bodies are showing their interest in physico-chemical characterization of APIs. Polymorphism is also important to be considered because this phenomenon is not exhibited by only drug molecule but also by other solid forms prepared by drug using crystal engineering approaches like salts, solvates, co-crystals etc. However, the discovery and genesis of various crystal forms is quite tiresome and expensive [9-12].

This chapter has focused on the various crystal forms of anti-diabetic agents and techniques employed in their preparation.

Diabetes mellitus is an unceasing disease in the society that requires life-long pharmacological and non-pharmacological management. Among this, type 2 diabetes mellitus is more prevalent. For the management of type 2 diabetes mellitus, various oral agents have been approved. The main problem of these agents is their dissolution limited bioavailability. To overcome this issue various attempts like CD complexes, solid dispersion, crystal engineering approaches and exploring the more soluble polymorphic form have been made.

2. Case studies of crystal forms of antidiabetics

Several crystalline forms of anti-diabetics have been described in the past. A general account of different crystal forms, their method of preparation along with transition / melting temperature are detailed in table 1.

3. Sulfonyluraeas

3.1. Acetohexamide

Potentiality of polymorphism in acetohexamide was first observed by Girgis-Takla and Chroneos in 1977. They reported two polymorphic forms (polymorphs A and B), distinguished by IR spectra and further characterized by Mueller and Lagas. However, forms showed no notable differenceon drying at 60°C in vaccum [13-14]. Graf et al. proposed keto-enoltautomerism for their stability, confirmed by IR spectra. Polymorph A (enol form) forms six membered ring via bonding of an O—H and S=O group intramolecularly while polymorph B (keto form) shows intermolecular bonding of C=O of urea to a sulphonamide N—H [15-16].

Kuroda et al. collected three crystal forms (Form I, Form II and CHCl3 – II) out of which one was found to be chloroform solvate. Form II was found to be 1.2 times more soluble than Form I [17].Yokoyama et al. estimated the thermodynamic values (transition temperature - 154°C & heat of transition - 230°C) of crystal forms (Form I and Form II) from solubility studies. Both forms were found equally bioavailable inbeagle dogs [18].Another forms Form IV by Graf et al and Form II and III by Al-Saieq and Rileywere investigated [19-20]. Later Graf et al. found that Form II was mixture of I and IV, while Form III (by Al-Saieq and Riley) on heating, converted to a new polymorph V [15].

Another crystal form of acetohexamide (Form VI) by Aldawsariet al. was reportedand was more soluble in water, and more bio-available in rats as compared to other already reported crystal forms [21].

3.2. Chlorpropamide

Various publications on the crystal forms (about 16) of chlorpropamide were reported (by Simmons et al., Burger et al., and Saieq et al.)[22-24], but the provided data could not distinguish existing crystal forms in actual [1-3]. Ueda et al. depicted convex shaped dissolution curve for Form C (by simmons et al.) and Form II (by saieq et al.)that indicates crystallization along with anhydrate to hydrate phase transformation [25].

After that, Debrushchaket al. adopted a new methodology for nomenclature (α, β, γ, δ, ε) on the basis of the order of their crystal structure established. Form α, β, γ and δ correspond to previously reported Form III, II, IV and VI respectively and was found that all forms transformed to ε (Form I) crystal form.On cooling up to 200 K, crystal form ε, converted to another new form (ε’). This new form resembled to α form in aspect of cell parameters and molecular conformation while to ε form in case of packing (Z shaped ribbons). Form α, β, γ has same intermolecular hydrogen bonding but differ in packing and number of molecules in unit cell [26-30].

Bifurcated intermolecular hydrogen bonding pattern of carbonyl group has been seen with the two amine hydrogen atoms, and SO2 oxygen atom acquires hydrogen from the nitrogen attached to alkyl tail.With regard to enthalpy of transition, conversion of α, β, γ and δ to ε should be in order of β > γ > δ > α but β polymorph infracts it because of structural difference [31].

All these polymorphs are conformational polymorphs as they showed difference in torsion angles. (as shown in figure 1) [32]


Figure 1.

Chlorpropamide with possible torsion angles [32]

Process of crystallization was also found to be affected by the presence or absence of 2-hydroxybutyl-β-cyclodextrin as chlorpropamide crystallized to metastable Form II and III in presence, whereasto Form A in the absence at 4C. Even the appearance of crystal form was dependent on the concentration and temperature [33].

3.3. Tolbutamide

Several Tolbutamide polymorphs are reported by several groups of workers. [34-42]. Two forms reported by Simmons et al[34] (Forms A and B) are identical with the Burger’s Form I and III [35], respectively, and have been well characterized. However, Burger’s Forms II and IV have been not fully characterized.

3.4. Glimepiride

Two polymorphs (Form I and II) are reported in literature. New crystalline form (Form II) was prepared by recrystallization from an ethanol/water system was found to have different dissolution profile and solubility [43] and it transformed to Form I over 140°C.

3.5. Glibenclamide

Crystallisation of glibenclamide from different solvents and quick cooling of melt gave three polymorphic forms and pseudopolymorphs (solvates), which were significantly different with regard to solubility and melting properties. [44-45] A new crystalline form of glibenclamide,with higher melting point (218°C) and lower solubility, was formed during an attempt to elucidate transitional phases by melting, cooling and reheating by A. Panagopoulou-Kaplani, et al[46].

4. Meglitinides

4.1. Nateglinide

Various solvates/ hydrates (about 26) of nateglinide have been patented which eventually converts to either Form B or Form H. [47] The S polymorph was crystallized from the melt or by isothermal treatment of B or H forms at temperatures higher than their melting points which is the only stable form, while the polymorphs B and H are metastable forms. The anhydrous polymorph, if stored at room temperature and humidity, gradually changes to H polymorph while, if stored in water vapour saturated atmosphere, it gets back water and reverts to the hemihydrate form. On the contrary, both an isothermal treatment at 80 ◦C and melt cooling bring to the B polymorph [48].

4.2. Repaglinide

S enantiomer of repaglinide was found active hypoglycemic agent andthree crystalline forms (Form I, II and III) were crystallized from various solvents by solvent/antisolvent and slow evaporation method. Form II (low melting crystal form) on further heating showed second melting endotherm at 127-130°C and converted to Form I if crystallized in ethanol/water mixture [49].

5. Biguanides

5.1. Metformin hydrochloride

Two polymorphs (form A and B) has been identified out of which form A is more thermodynamically more stable while highly metastable structure, which correlates with the difficulty in handling this polymorph [50]. These two polymorphs and their mixture has been evaluated by Scott L. Childs, et al using capillary crystallization and thermal microscopy techniques. Crystal structure of these forms arereported [51]. Both structures are monoclinic (P21/c) with one complete metformin cation and one chloride anion in the asymmetric unit as shown in figure 2.


Figure 2.

Metformin hydrochloride Form A and B shown, respectively at 50% probability ellipsoids. [50]

6. Thiazolididiones

6.1. Rosiglitazone

Various crystalline forms of maleate salt of rosiglitazone are reported in literature. Choudary et al. and Blackler et al. put illumination on crystalline hydrates of salt [52-54]. Chebiyyam et al. described four crystalline forms (Form I, II, III and IN) while Birari et al. described two forms (Form A and B). Form A was detected more stable than B and all the other crystal forms, amorphous form, hydrate and anhydrate converted to Form A [55-56]. Kansalet al. depicted three crystal forms (Form I, III and IV) for hydrobromide salt of rosiglitazone and formulated Form III in compacted dosage form, while Greil et al. elaborated two hydrates (Form A and C), one solvate (Form D) and three anhydrate (Form B, B1 and E). 1:1 hydrates were recovered which may lose their water content at different temperature. Form B and B1 have shown same melting endotherm temperature but they were distinguished by PXRD [57-58].

6.2. Pioglitazone hydrochloride

Only two polymorphic form I and II has been evaluated which are patented [59].

6.3. Troglitazone

Various crystalline forms of troglitazone are patented. Polymorphs 1,2,3 and 6 are obtained by different modes of recrystallization while form 4 and 5 are derived by heating any one of the form 1, 2, 3 or 6 [60].

7. Dipeptidyl peptidase-4 inhibitor

7.1. Alogliptin

In literature, six crystal forms of tartrate (Form A, B, C, D, E and F) and one crystalline form of benzoate salt of alogliptin (Form A) were reported. Among the crystal forms of alogliptin tartrate, Form A was found to be more stable and all forms during stability studies converted to Form A. The most stable form were analyzed for solubility and alsoestablished thermally stable up to 200°C and a variable hydrate.

Form A of benzoate salt was found to be much stable and amorphous form converted to stable Form A during heating [61-62].

7.2. Linagliptin benzoate

Crystalline forms of linagliptin benzoate have been patented. Form II is less hygroscopic then Form I. Thus, can be easily handled in standard pharmaceutical processing conditions and no special packing is required during its storage [63].

7.3. Sitagliptin

Numerous solvates and crystal forms of sitagliptin phosphate have been patented. All the reported crystalline solvates converted to Form II on desolvation and on heating metastable Form II converted to Form I (at 45°C) and to Form III at 110°C. Form I (stable at higher temperature) and Form III (stable at lower temperature) have enantiotropic relation [64]. Form IV, also a metastable form, slowly converted to crystalline sitagliptin phosphate monohydrate [65]. Huang et al. prepared Form V and processed them to pharmaceutical formulation [66].

7.4. Saxagliptin

Monohydrate, hemihydrates and mixture of thereof of saxagliptin had been prepared and patented [67].Nine polymorphic forms of saxagliptin hydrochloride (Form K, T, Z, N, S, O, B, C and D) had been evaluated either from its amorphous form or dihyrate form and being patented. Forms K, S, N and Z are polymorphically pure, Form D is a hydrate, Form T is in a mixture with ammonium chloride, Form O is in a mixture with form K and saxagliptinmonochydrochloridemonohydtare while Form B is in a mixture with saxagliptinmonochydrochloridedihyrate [68]

Drug Crystal form Solvent used Method of preparation Transition (T)/ Melting endotherms(M) References
Polymorph AGlacial acetic acidSlow evaporation180-183°C[13]
Polymorph BChloroformSlow evaporation183-185°C
Form I (triclinic)Ethanol/ methanol/ acetoneSlow evaporation187°C[17]
Form II (monoclinic)Ethanol: water (1:1)Heating, slow evaporation157°C (T), 186°C (M)
CHCl3 – IIHot chloroformSlow evaporation164–169°C (T), 182°C (M)
Form IVHot benzeneSlow evaporation184-186°C[19]
Form II (mixture of I and IV)Hot IsobutanolSlow evaporation176-178°C[20]
Form IIIChloroformRapid cooling of saturated solution at 55°C-
Form V-Heating Form III at 160°C -[19]
Form VIHP-β-CD in sodium phosphate buffer of pH 8.0Titration to 0.5 M HCl, filteration, cooling-[21]
Form A/ III/ /IVEthanol-water mixtureSlow evaporation121-122°C[22-24]
Form B /II /V-Recystallization from melt of Form A124-127°C
Form C /I-Heat Form A at 120°C128-130°C
Form IVCarbon tetrachlorideSlow evaporation122-123°C[23]
Form VBenzeneDesolvation of benzene solvate< 118°C
Form IIChloroformRapid evaporation-[24]
Form IIIHexanolRapid cooling-
Form α
EthanolSlow evaporation124°C (T), 127-128°C (M)[26]
Form β (orthorhombic)Heptane-ethyl acetateSolvent-antisolvent addition125-127°C[27]
Form γ (monoclinic)Heptanes: ethyl acetate (1:2)Freezing at -20°C120°C (T), 128°C (M)
Form δ (orthorhombic)Heptanes: ethyl acetate (2:1)Slow evaporation124°C (T), 128°C (M)
Form ε (orthorhombic)-Solid transformation of Form α128°C
Form IBenzene: hexane (2:1)Solvent-antisolvent addition, slow evaporation127°C[38]
Form II-Form IV stored at 60°C, 75% RH, 10min.100°C (T), 127°C (M)
Form IIIEthanol: water (2:1)Solvent-antisolvent addition, slow evaporation113°C (T), 127°C (M)
Form IVEthanol: DCM (1.2:1)Spray drying80°C, 100°C (T), 127°C (M)
Form VConc. HNO3, methanolCocrystallisation with p-nitrophenol, p-phenylenediboronic Acid in ethanol-[69]
GLIMEPIRIDEmedia/image6.png Form IEthanol and chloroformSlow evaporation207°C[43]
Form IIEthanol: water (1:1)Heating, slow evaporation140°C (T), 207°C (M)[70]
Form I-Slow evaporation174°C[45]
Form III-Slow evaporation153°C
Solvatepentanol/ touleneSlow evaporation109°C[44]
New Form-Sublimation of glassy state at 130-160 °C218 °C[46]
Glassy form-Quench cooling of melt42- 56°C (T), 90-135°C (exotherm), 198°C (M)
Form BMethanol: water (7:3)Cooling at 10°C128-130°C[71]
Form HAcetone: water (2:3)Cooling at 10°C138-141°C
Form S-Melting/ isothermal treatment of Form B/H172 °C[48]
Form IEthanol/water (2:1), acetone/pet ether, methanol/water, THF/MTBE, ethyl acetate/pet ether, n-propanol/water, ACN/water, MIBK/MTB, diethyl ketone/MTB, t-butanol/water, methyl ethyl ketone/n-heptane, diglyme/n-heptane, methyl ethyl ketone/MTBE, 1,4-dioxane/n-heptane, n-butanol/MTBE, chloroform/n-hexaneSolvent-antisolvent, slow evaporation130-131°C[49]
Form IIPet ether: toluene (5:3)Rapid cooling99-101°C
TolueneHeating followed by cooling
Form III (from Form I, II and amorphous form)Dichloromethane and pet etherCooling and stirring80-84°C
Form AMethanol: water (2:1)slow evaporation-[50]
Form BAcetone: water (3:1)slow evaporation-
HydrateAcetonitrile: water (30:1)/ THF: water (30:1)/ methyl ethyl ketone: water (30:1)/ ethyl acetate: water (100:1)/ isopropanol: water (33:1)Heating followed by cooling-[52]
HydrateEthanol and water (2.1%v/v)Heating followed by cooling
Methanol-water/acetonitrile-water/ ethanol-waterHeating followed by cooling
Methanol-waterHeating followed by cooling
WaterHeating followed by cooling
Ethyl acetate-waterHeating followed by cooling
Form IEthanolHeating followed by cooling100.53°C[55]
Form IIAcetoneHeating followed by cooling127.67°C
Form IIIMethanolHeating followed by cooling126.41°C
Form IN1,4-dioxaneHeating followed by cooling125.39°C
Form AMethanol-ethyl acetateHeating solution in methanol followed by addition of ethyl acetate [56]
AcetonitrileHeating the solution followed by reflux and cooled
Form BIsopropyl alcoholHeating followed by cooling-
MethanolAddition of methanol to acetone solution of salt
Isopropyl alcohol / THFHeating of Suspension of Form A followed by cooling
-Heating followed by cooling
Form IAcetoneReflux, cooling-[57]
Form IIIDemineralised waterReflux, cooling-
Form IVAcetoneHeating Form I in acetone-
Form AAcetone and waterStirring of suspension171-177°C[58]
Ethanol and waterStirring of suspension
Form BAcetone and waterStirring of suspension175-176°C
Form B1-Stirring of suspension175-176°C
Form CAcetone: water (1:1)Phosphoric acid added to solution of Form B-
Stirring of suspension of Form A
Form DMethanolHeating of suspension of Form A-
Form EEthanolHeating followed by cooling167-172°C
Form IDMF/ Methanol/ acetic acidHeating followed by cooling198°C[59]
Form IIAcetic acid, waterHeating followed by cooling183°C
Form 1Benzene: acetone (100: 1)Slow evaporation179°C[60]
Form 2Benzene extraction, DCM addedFast evaporation at -10°C110°C (T), 175°C (M)
Form 3Acetone: benzene (1:2)Cooling at 5°C185°C
Form 4-Form I heated to melt56°C (T), 110 °C (exotherm), 177°C (M)
Form 5-Heating of Form IV at 130 °C157°C (exotherm), 180°C (M)
Form 6Acetone: benzene (1:4)Cooling of solution of Form I at 5 °C105°C
Form AAcetone: water (2:3) or methanolFiltration, slow evaporation172.5°C[61]
Hot methanol and acetone/ methanol and tolueneCold acetone/toluene was added in filtered solution of hot methanol and alogliptin tartrate, slow evaporation
waterHeating, slow evaporation
Form BTetrahydrofuran: water (2:1)/ dioxane: water (2:1) / acetonitrile: water (4:3)Filtration, slow evaporation124.4°C
Form CEthanol: water (1:1) / isopropanol: water (1:1)Filtration, slow evaporation122.4°C
Form DwaterHeating at 80°C, filtered and cooling 173.3°C
methanolPlaced amorphous form with methanol in sealed chamber for several weeks
Form EWater: acetonitrile (4:21) / water: dioxane (2:1)Heating at 50°C, filtered, slow evaporation 121.9°C
Form F-Placed amorphous form with saturated salt solution at 84% RH in sealed chamber -
Form AAcetone / MethanolFiltration, fast evaporation186°C[62]
AcetonitrileHeating slurry at 60°C, filtration, slow evaporation
Ethanol: isopropyl acetate (99:1)Reflux, cooling
Form IIsopropanolSlow evaporation
Form IIAcetonitrileSlow evaporation193°C
SolvateMethanol/ ethanol/ 1-propanol/ 2-propanol/ acetone/ acedtonitrileBy contacting with solvent for 5 minutes213.61°C[64]
Form IIsoamyl alcohol/waterSlow evaporation215.37°C (T), 217.27°C (M)
Form II-Desolvation of ethanol solvate114.6°C (T), 213.80°C (M)
Form IIIIsoamyl alcohol/waterSlow evaporation80.90°C (T), 215.94°C (M)
Form IV-Heating monohydrate form above 58°C213.3°C[65]
Form VMethanol-water/ acetone-waterHeating followed by cooling214.88°C[66]
Methanol, n-butanone, THF, ACN, DMC and waterDistillation at 55°C
Form H-1 (monohydrate)EthanolKept in desiccator in atmosphere of respective solvents-[67]
Water, 80% RH
Form KEthyl acetate, Conc. HClReflux, cooling-[68]
Form TSaturated ammonium chloride pH 4.53Precipitation-
Form Z (Dihydrate)Ethyl alcohol, MethylisopropylketonePrecipitation
Form N2- butanolReflux, cooling-
Form SWet ethyl acetate, Conc. HClHeating followed by cooling-
Form O0.8 M HCl/ Ethyl alcoholHeating followed by cooling-
Form BEthyl alcohol, Methylethylketonestirring-
Form CPropyl alcoholHeating followed by cooling-
Form D (hydrate)1-butanolHeating, stirring-

Table 1.

Crystalline Forms of Antidiabetics

8. Conclusion

The crystallization process has profound impact on crystal forms, which further affect biopharmaceutical properties of pharmaceutical solids. Various crystal forms of antidiabetics have been reported in literature and some have even gained the status of a patent. The existence of these different crystal forms are possible due to presence of sulphoxamide, carboxamide, thiazolidendione, etc. groups in these agents. For the optimized pharmaceutical acceptable solid form, one must be cognizant of the potentiality of an API to exist in various crystal forms by altering the crystallization conditions. Because of this, screening of new crystal forms of API’s has become a vital part of drug discovery and development in past decade.


Authors are grateful to Council of Scientific and Industrial Research, New Delhi for their financial support under project scheme 02(0039)/11/EMR-II.


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