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

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].


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 nonsolvent 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][10][11][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.
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  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].
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][27][28][29][30].
Bifurcated intermolecular hydrogen bonding pattern of carbonyl group has been seen with the two amine hydrogen atoms, and SO 2 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] [32] Process of crystallization was also found to be affected by the presence or absence of 2hydroxybutyl-β-cyclodextrin as chlorpropamide crystallized to metastable Form II and III in presence, whereasto Form A in the absence at 4 • C. Even the appearance of crystal form was dependent on the concentration and temperature [33].

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.

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].

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].

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].

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.
method. Form II (low melting crystal form) on further heating showed second melting endotherm 127-130°C and converted to Form I if crystallized in ethanol/water mixture [49].

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

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

Troglitazone
Various crystalline forms of troglitazone are patented.

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].

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].

Saxagliptin
Monohydrate, hemihydrates and mixture of thereof of saxagliptin had been prepared and patented [67].

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.