Acalabrutinib, an anti-cancer drug, was approved by the USFDA in 2017. However, the acalabrutinib capsules (marketed as CALQUENCE) posed certain challenges for cancer patients. To overcome these issues, the brand company developed acalabrutinib maleate tablets, which received USFDA approval in 2022. While acalabrutinib has multiple solid forms, acalabrutinib maleate salt exists only as a hydrate. This study addressed the literature discrepancy regarding acalabrutinib maleate whether it is a monohydrate or sesquihydrate. It also aimed to develop a novel solid form of acalabrutinib maleate salt with improved or comparable physicochemical properties to meet the unmet needs of cancer patients. This is the first study to report a new solid form, specifically a pharmaceutically acceptable solvate of acalabrutinib maleate, and to conduct its structural investigation. Various analytical tools, including X-ray diffraction (powder XRD and single crystal XRD), spectroscopy (1H-NMR and HPLC), thermal analyses (DSC and TGA), and physicochemical characterization (solubility and stability), were used to investigate the properties of the new solid form. The physicochemical studies indicated that the new solid form of acalabrutinib maleate has similar solubility to its commercial form and remained stable after a six-month study under FDA-recommended storage conditions. To the best of our knowledge, this is the first time the reason for similar solubility has been linked to isostructurality, using Hirshfeld surface and Xpac analysis. Therefore, the novel, stable, and scalable new solid form discussed in this study is a potential candidate for early market launch due to its similar properties to the commercial form.

Niraparib is an anti-cancer drug marketed as a tosylate monohydrate salt (brand name ZEJULA). Although it was approved by USFDA and the European Union in 2017, niraparib tosylate is known to exist in only three solid forms till today. Amongst the three, the monohydrate is a stable form and the other two (anhydrous and non-stoichiometric hydrate) forms are quite unstable. Despite niraparib's potential value as a cancer treatment drug, there are currently very limited or no scientific reports on its solid form landscape. In this regard, this molecule has been chosen as a potential candidate for our research to find alternative solid forms that suite the early entry opportunity in the US or other generic markets. In this study, we initially investigated the reasons for the unstable nature of niraparib tosylate polymorphs other than its monohydrate. Further, we successfully synthesized a novel multicomponent solid form of niraparib tosylate with l-proline (NIR center dot TOS center dot PRO). Interestingly, the new multi-component solid is a "zwitterionic salt-cocrystal". To the best of our knowledge, this is the first case study reporting a zwitterionic salt-cocrystal. Preliminarily, the salt-cocrystal was characterized using powder X-ray diffraction and differential scanning calorimetry. Further, we carried out the structural elucidation for niraparib tosylate monohydrate as well as the new salt-cocrystal using single-crystal X-ray diffraction. The new salt-cocrystal was subjected to powder dissolution studies at pH 1.2, pH 4.5, and pH 6.8 to compare with the marketed form, "niraparib tosylate monohydrate (NIR center dot TOS center dot H2O)". Six-month stability studies were also performed according to the ICH guidelines. The solubility of NIR center dot TOS center dot PRO is found to be the same as that of the marketed form, which is an advantage in meeting the criteria of bioequivalence with RLD (reference listed drug), essentially to obtain the regulatory approval for US or other generic markets.

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.

Suvorexant (SRX) is a dual orexin receptor antagonist used for the treatment of insomnia.

The non-steroidal anti-inflammatory drugs mefenamic acid (MFA) and tolfenamic acid (TFA) have a close resemblance in their molecular scaffold, whereby a methyl group in MFA is substituted by a chloro group in TFA. The present study demonstrates the isomorphous nature of these compounds in a series of their multicomponent solids. Furthermore, the unique nature of MFA and TFA has been demonstrated while excavating their alternate solid forms in that, by varying the drug (MFA or TFA) to coformer [4-di-methyl-amino-pyridine (DMAP)] stoichiometric ratio, both drugs have produced three different types of multicomponent crystals, viz. salt (1:1; API to coformer ratio), salt hydrate (1:1:1) and cocrystal salt (2:1). Interestingly, as anticipated from the close similarity of TFA and MFA structures, these multicomponent solids have shown an isomorphous relation. A thorough characterization and structural investigation of the new multicomponent forms of MFA and TFA revealed their similarity in terms of space group and structural packing with isomorphic nature among the pairs. Herein, the experimental results are generalized in a broader perspective for predictably identifying any possible new forms of comparable compounds by mapping their crystal structure landscapes. The utility of such an approach is evident from the identification of polymorph VI of TFA from hetero-seeding with isomorphous MFA form I from acetone-methanol (1:1) solution. That aside, a pseudopolymorph of TFA with di-methyl-formamide (DMF) was obtained, which also has some structural similarity to that of the solvate MFA:DMF. These new isostructural pairs are discussed in the context of solid form screening using structural landscape similarity.

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 castration-resistant prostate cancer (mCRPC). ABI is administered orally at a high dosage of 1 g/day (four 250 mg tablets) and has an issue of poor solubility. The combination of high dose and poor aqueous solubility/dissolution properties make the compound a candidate for salt/cocrystal work. To date, there are no reports on solid-state modification (salts/cocrystals) of ABI using a crystal engineering approach. In this regard, we applied an in silico (COSMOtherm-X) method, as well as Delta pK(a) index, to identify suitable GRAS coformers (generally regarded as safe coformers approved by the US FDA) to form cocrystals with abiraterone acetate (ABI), which is used as a model drug compound in this study. Solvent assisted cogrinding and crystallization of abiraterone acetate (ABI) with high solubility coformers resulted in four cocrystals with succinic acid (SA), glutaric acid (GA), 4-hydroxy benzoic acid (4HBA), and 3,5-dihydroxy benzoic acid (35DHBA). The parent drug ABI and cocrystals ABI-SA (2:1), ABI-GA (1:1), ABI-4HBA (1:1), and ABI-35DHBA (1:1) were characterized using various techniques. Diffraction quality single crystals could be grown for cocrystals ABI-GA (1:1) and ABI-4HBA (1:1) for structure determination, while solid phase purity for the other two cocrystals was proven with powder indexing analysis using material studio. Incidentally, ABI-GA (1:1) forms a supercell (Z = 12 and Z' = 6). Moreover, it shows a highest dissolution rate of 31-fold as compared with the parent ABI (120 min interval) at pH 1.2 buffer conditions. Investigation of ABI-GA (1:1) high dissolution rate as compared with other cocrystals, stability studies (forced degradation), and reasons for supercell formation (ABI-GA (1:1)) are also discussed in detail.

We report the solid-state structural properties and phase transition behavior of 1,4-dibromo-2,3,5,6-tetramethylbenzene, demonstrating that this material undergoes an order disorder phase transition below ambient temperature (at ca. 154 K on cooling and ca. 160 K on heating). In both the high-temperature and low-temperature phases, the crystal structure is based on pi-stacking of the molecules. In the crystal structure of the high-temperature phase, the bromine occupancy in each substituent site is ca. 1/3 and the methyl group occupancy in each substituent site is ca. 2/3, consistent with statistical orientational disorder of the molecule between six distinct orientations. Natural-abundance solid-state H-2 NMR spectroscopy confirms that, at ambient temperature, this disorder is dynamic via rapid molecular reorientation about an axis perpendicular to the aromatic ring. In the low-temperature phase, the bromine and methyl substituents occupy preferred sites within the crystal structure, with the distribution of site occupancies becoming progressively more ordered on decreasing temperature.

Molecular crystals are not known to be as stiff as metals, composites and ceramics. Here we report an exceptional mechanical stiffness and high hardness in a known elastically bendable organic cocrystal [caffeine (CAF), 4-chloro-3-nitrobenzoic acid (CNB) and methanol (1:1:1)] which is comparable to certain low-density metals. Spatially resolved atomic level studies reveal that the mechanically interlocked weak hydrogen bond networks which are separated by dispersive interactions give rise to these mechanical properties. Upon bending, the crystals significantly conserve the overall energy by efficient redistribution of stress while perturbations in hydrogen bonds are compensated by strengthened π -stacking. Furthermore we report a remarkable stiffening and hardening in the elastically bent crystal. Hence, mechanically interlocked architectures provide an unexplored route to reach new mechanical limits and adaptability in organic crystals. This proof of concept inspires the design of light-weight, stiff crystalline organics with potential to rival certain inorganics, which currently seem inconceivable.

Distinct macroscopic mechanical responses of the three crystals of naphthalene diimide derivatives, 1Me, 1Et, and 1nPr, studied here are very intriguing because their molecular structures are very similar, with the difference only in the alkyl chain length. Among the three crystals examined, 1Me shows highly plastic bending nature, 1Et shows elastic flexibility, and 1nPr is brittle. A detailed investigation by nanoindentation and molecular dynamics (MD) simulations allowed us to correlate their distinct mechanical responses with the way the weak interactions pack in crystal structures. The elastic modulus (E) of 1Me is nearly an order of magnitude lower than that of 1Et, whereas hardness (H) is less than half. The low values of E and H of 1Me indicate that these crystals are highly compliant and offer a low resistance to plastic flow. As the knowledge of hardness and elastic modulus of molecular crystals alone is insufficient to capture their macroscopic mechanical deformation nature, that is, elastic, brittle, or plastic, we have employed three-point bending tests using the nanoindentation technique. This allowed a quantitative evaluation of flexibility of the three mechanically distinct semiconducting molecular crystals, which is important for designing larger-scale applications; these were complemented with detailed MD simulations. The elastic 1Et crystals showed remarkable flexibility even after 1000 cycles. The results emphasize that the alkyl side chains in functional organic crystals may be exploited for tuning their self-assembly as well as their mechanical properties. Hence, the study has broad implications, for example, in crystal engineering of various flexible, ordered molecular materials.

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTVisible Light Mediated Photopolymerization in Single Crystals: Photomechanical Bending and Thermomechanical UnbendingRanita Samanta†, Subhrokoli Ghosh‡, Ramesh Devarapalli†, and C. Malla Reddy*†View Author Information† Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur Campus, Mohanpur 741246, India‡ Department of Physical Sciences, Indian Institute of Science Education and Research (IISER) Kolkata, Mohanpur Campus, Mohanpur 741246, India*C. Malla Reddy. E-mail: [email protected]Cite this: Chem. Mater. 2018, 30, 3, 577–581Publication Date (Web):January 12, 2018Publication History Received12 November 2017Revised12 January 2018Published online19 January 2018Published inissue 13 February 2018https://pubs.acs.org/doi/10.1021/acs.chemmater.7b04756https://doi.org/10.1021/acs.chemmater.7b04756rapid-communicationACS PublicationsCopyright © 2018 American Chemical SocietyRequest reuse permissionsArticle Views2804Altmetric-Citations65LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (5)»Supporting Information Supporting Information SUBJECTS:Crystal structure,Crystals,Electromagnetic radiation,Monomers,Polymers Get e-Alerts

Materials that respond to external stimuli like heat, light, and pressure are of immense importance in the conversion of respective energy to mechanical work.Such mechanically responsive materials are candidates for future dynamically active elements like artificial muscles, actuators, heat-responsive materials for electronics, sensors, and others.Single crystalline materials may be utilized fully in the development of technologically valuable actuators because of their highly ordered structures and ability of fast energy transport.However, the relationship between the changes in the crystal mechanical properties and crystal structure during a phase transition has remained relatively unexplored.In this study, a single-crystalto-single-crystal phase transformation by heat as an external stimulus for two plastically bendable (under mechanical stress) isomorphous Schiff bases is studied by both experiments and molecular modeling simulations.Upon heating, the compounds viz.o-vanilidene-p-chloroaniline and o-vanilidene-p-bromoaniline were irreversibly converted to new polymorphs; interestingly these are also isomorphous as revealed by their cell parameters.The thermosalient effect of these two compounds was fully studied with the help of variable temperature single crystal X-ray structure determination, thermal analysis and with variable temperature powder X-ray diffraction data.The plastically bendable parent crystals convert to brittle polymorphs after phase transition.The plasticity and hardness of polymorphs were quantified with the nanoindentation technique.The reasons for such gratuitous mechanical properties were deeply investigated.

In crystal engineering, the isostructurality and isomorphism aspects are relatively unexplored compared to the common phenomenon, polymorphism.Two crystals are said to be isostructural if they have the same crystal structure, but not necessarily the same cell dimension nor the same chemical composition.On the other hand two crystals are said to be isomorphous if both have the same space group and unit-cell dimensions.In the family of fenamates, mefenamic acid (MFA) and tolfenamic acid (TFA) are isostructural and known to exist in multiple polymorphs.Amongst the polymorphs of these two fenamates, form-II of MFA and form-V of TFA are isomorphous.Herein, we explore the existence of this isomorphous nature in the multicomponent solids polymorphs of MFA and TFA by taking aid from their crystal structural landscape.In this process, we have synthesized three such new isomorphous multicomponent solid pairs with the commercially available MFA and TFA samples.The multicomponent solids include salt (1:1), co-crystal salt (2:1) and salt monohydrate (1:1:1) of MFA and TFA with 4-dimethylaminopyridine (DMAP).Thereafter the new solid forms were thoroughly characterized with several characterization techniques and their structural relationship was investigated.Among them the single crystal diffraction results show that the new solid form pairs of the same ratio (for e.g.1:1 salts of MFA and TFA) possess same space group and structural packing, which implies that they retain isomorphous nature alike their parent APIs, MFA and TFA.In the course of this study, we realized a tremendous use of mapping the structural landscapes of the two isomorphic series, for instance to obtain the new (or hidden) polymorphs of isostructural pairs.In the quest to validate this utility, we discovered a sixth polymorph and a pseudopolymorph of TFA.[1]

Hydrochlorothiazide (HCT) is a diuretic BCS class IV drug with poor aqueous solubility and low permeability leading to poor oral absorption. The present work explores the cocrystallization technique to enhance the aqueous solubility of HCT. Three new cocrystals of HCT with water soluble coformers phenazine (PHEN), 4-dimethylaminopyridine (DMAP) and picolinamide (PICA) were prepared successfully by solution crystallization method and characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), fourier transform -infraredspectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Structural characterization revealed that the cocrystals with PHEN, DMAP and PICA exists in P2(1)/n, P2(1)/c and P2(1)/n space groups, respectively. The improved solubility of HCT-DMAP (4 fold) and HCT-PHEN (1.4 fold) cocrystals whereas decreased solubility of HCT-PICA (0.5 fold) as compared to the free drug were determined after 4 h in phosphate buffer, pH 7.4, at 25 degrees C by using shaking flask method. HCT-DMAP showed a significant increase in solubility than all previously reported cocrystals of HO' suggest the role of a coformer. The study demonstrates that the selection of coformer could have pronounced impact on the physicochemical properties of HO' and cocrystallization can be a promising approach to improve aqueous solubility of drugs. (C) 2016 Elsevier B.V. All rights reserved.

Controlling mechanical properties of ordered organic materials remains a formidable challenge, despite their great potential for high performance mechanical actuators, transistors, solar cells, photonics, and bioelectronics. Here we demonstrate a crystal engineering approach to design mechanically reconfigurable, plastically flexible single crystals (of about 10) of three unrelated types of compounds by introducing active slip planes in structures via different noninterfering supramolecular weak interactions, namely van der Waals (vdW), π-stacking, and hydrogen bonding groups. Spherical hydrophobic groups, which assemble via shape complementarity (shape synthons), reliably form low energy slip planes, thus facilitating an impressive mechanical flexibility, which allowed molding the crystals into alphabetical characters to spell out "o r g a n i c c r y s t a l". The study, which reports the preparation of a series of exotic plastic crystals by design for the first time, demonstrates the potential of soft interactions for tuning the mechanical behavior of ordered molecular materials, including those from π-conjugated systems.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.