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Achieving the desired solubility and dissolution of active pharmaceutical ingredients (APIs) continues to be a big challenge in the pharmaceutical industry. In this regard, multicomponent solids of APIs such as salts and cocrystals have shown significant promise in resolving such solubility/dissolution issues. However, very little is known on how the APIs' solubility or dissolution is affected by the drug to coformer ratio in multicomponent solids. Betrixaban, is an anticoagulant drug approved in 2017 for the prevention of venous thromboembolism. During the alternate solid form development studies of the known betrixaban maleate, a rare multicomponent solid form, salt-cocrystal hydrate of betrixaban, was discovered and characterized thoroughly by spectroscopic, thermal, and X-ray crystallographic methods. Significantly, the new betrixaban maleate maleic acid hydrate (1:1:2:1) form has shown lower melting point (80 °C) as compared to its parent salt (197.5 °C). From such a large melting difference (117 °C) between the salt and salt-cocrystal hydrate of API, we anticipated substantially better solubility for the salt-cocrystal hydrate (low enthalpy). Furthermore, the predicted solubility also supported our anticipation. However, the powder dissolution tests at different pH conditions provided contrary results, that is, the salt-cocrystal hydrate showed 10 times lower solubility as compared to its salt. A detailed investigation, considering all the potential factors, revealed that "common-ion effect" could be a critical factor for the low solubility of the salt-cocrystal hydrate in which the API to coformer ratio is 1:3. To the best of our knowledge, this is the first case study on the solubility of pharmaceutical salt-cocrystal hydrates with an emphasis on "common-ion effect" or drug to coformer ratio. more...

Suvorexant (SRX) is a dual orexin receptor antagonist used for the treatment of insomnia. It belongs to the Biopharmaceutics Classification System (BCS) class II with high permeability and poor solubility in water (0.024 mg mL−1). It is a very challenging molecule from the crystallization perspective because most of the crystallization experiments predominantly yield either form I or a semi-solid form. Increasing S-enantiomer impurity is another problem that was observed during the recrystallization. Further to this, SRX is known to exist in only two crystalline polymorphs (forms I and II). As far as we know, there is no report on the crystal structure analysis or the solid-state modification approaches pertaining to the suvorexant molecule. All these critical aspects of suvorexant have drawn our attention towards the development of novel solid forms by using crystal engineering principles. Here, we report two novel salts and one salt solvate of suvorexant with p-toluenesulfonic acid (PTSA) and benzenesulfonic acid (BSA) with the objective of enhancing the solubility and dissolution. All three solid forms were characterized by powder XRD, DSC, FT-IR, and single crystal XRD. Notably, the BSA salt crystallizes as an anhydrous form and the PTSA salt of suvorexant crystallizes as a methanol solvate. Furthermore, the methanol solvate of the PTSA salt shows an efficient single-crystal-to-single-crystal phase transformation to the anhydrous form upon heating, yielding X-ray diffraction quality single crystals. In view of the pharmaceutical importance of these salts, we have performed pH solubility and intrinsic dissolution rate (IDR) studies in comparison to the marketed form. The novel salts of suvorexant exhibit enhanced solubility in comparison to the marketed form II. Therefore, the novel salts are expected to show better formulation development. more...

Abiraterone acetate (ABI) is a BCS class IV (low solubility and low permeability) drug, and it was approved by the US FDA with brand name Zytiga in April 2011 for patients suffering from metastatic... more...

Ceritinib is an anaplastic lymphoma kinase (ALK) inhibitor used for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). This BCS class IV drug is developed by Novartis and traded under the name Zykadia. To date two forms [Form A (marketed form) and B] of ceritinib are disclosed in international patent application US 2013/0274279 A1. However, the crystal structure and insight into any solid form of this compound are not available in the literature. In order to achieve better physicochemical properties compared to known solid forms of this compound, novel polymorph identification is chosen as one of the challenging paths to address the issue. In our comprehensive polymorph screening, including in silico and experimental investigations, we discovered three novel solid forms of ceritinib. Out of these three solid forms, two are neat (Form 1 and Form 3) and the remaining one is a hydrate (Form 2). All synthesized forms are further characterized by powder X-ray diffraction, differential... more...

Lenalidomide (LDM) is a thalidomide analogue known for its immunomodulation, antiangiogenic, and antineoplastic properties. However, to date, only two forms of lenalidomide [Form-1 (anhydrous) and Form-2 (hemihydrate)] are reported in the literature. Through a comprehensive polymorph screening herein, we report five forms of lenalidomide [Form-3 (DMF-solvate), Form-4 (anhydrous), Form-5 (DMSO solvate), Form-6 (acetone solvate), and Form-7 (dihydrate)]. Single crystal structures (for all forms) are established to provide potential knowledge about the intermolecular interactions, three-dimensional structures, and the nature of solvent/water within the lattice. Thermodynamic stability investigations revealed unusual solid state phase transformations which are relatively unexplored to date. It is noteworthy that all solvates upon desolvation convert to Form-1 (thermodynamically stable anhydrous form), whereas all hydrates upon dehydration convert to a metastable Form-4 (novel anhydrous form) which, upon furth... more...

Two polymorphs Form-R2 and Form-R4 of anhydrous thymine, one of the four nucleobases in the nucleic acid of DNA were obtained via sublimation crystallization and desolvation technique respectively. Form-R2 crystallizes in monoclinic C 2/c with a = 25.107(7) A, b = 6.846(2) A, c = 6.715(2) A, β = 90.529(6)⁰ and V = 1154.1(5) A3. The supramolecular assembly in Form-R2 is a sheet of hydrogen bonded network similar to that found in the crystal structures of other reported anhydrous form of thymine (Form-R1). Interestingly the thermal behavior is similar for these two forms with a minor difference in powder X-ray diffraction pattern. Further thymine Form-R2 closely matches with one of the predicted form of thymine using Polymorph module of Accelrys. Form-R4 is obtained by the dehydration of the mono hydrated form (Form-R3) and characterized by powder X-ray diffraction, FTIR spectroscopic techniques and thermal analysis. more...

In this study, ultrasound-assisted alkaline pretreatment is developed to evaluate the morphological and structural changes that occur during pretreatment of cellulose, and its effect on glucose production via enzymatic hydrolysis. The pretreated samples were characterized using scanning electron microscopy, infrared spectroscopy, and X-ray diffraction to understand the change in surface morphology, crystallinity and the fraction of cellulose Iβ and cellulose II. The combined pretreatment led to a great disruption of cellulose particles along with the formation of large pores and partial fibrillation. The effects of ultrasound irradiation time (2, 4 h), NaOH concentration (1–10 wt%), initial particle size (20–180 μm) and initial degree of polymerization (DP) of cellulose on structural changes and glucose yields were evaluated. The alkaline ultrasonic pretreatment resulted in a significant decrease in particle size of cellulose, besides significantly reducing the treatment time and NaOH concentration required to achieve a low crystallinity of cellulose. More than 2.5 times improvement in glucose yield was observed with 10 wt% NaOH and 4 h of sonication, compared to untreated samples. The glucose yields increased with increase in initial particle size of cellulose, while DP had no effect on glucose yields. The glucose yields exhibited an increasing tendency with increase in cellulose II fraction as a result of combined pretreatment. more...

In the title compound, C11H5Br2ClO3, the benzopyran ring system is essentially planar (r.m.s. deviation = 0.023 Å) and one of the bromine atoms is almost coplanar with it [deviation = 0.091 (1) Å]. In the crystal, inversion dimers linked by pairs of double-acceptor (C—H)2...O hydrogen bonds are seen. Further C—H...O interactions link the dimers into (010) sheets. more...