Impact of Nisoldipine Crystal Morphology on Its Biopharmaceutical Properties: A Layer Docking Assisted Study

Crystal morphology or habit modification can have profound influence on the pharmaceutical and biopharmaceutical properties of active pharmaceutical ingredients. The effect of crystallization medium on nisoldipine (NSL) crystal habit was studied, wherein modified habits were observed in solvent system, methanol, and solvent antisolvent system of acetonitrile–IPA. Modified crystal habits of NSL were in correlation with the simulated habits in terms of their shape and aspect ratio. The comparative dissolution rate of the recrystallized NSL habits was in the order of NSL-M (NSL recrystallized with methanol) > NSL-AI (NSL recrystallized with acetonitrile and IPA) > NSL (plain NSL). A statistically significant (<i>p</i> < 0.05) enhancement in the dissolution rate of NSL-M was observed on comparison with NSL. NSL-M also exhibited a significantly higher <i>C</i>_max than NSL in an oral bioavailability study. The study of specific surface area values of important facets of NSL-M revealed a notable enhancement of the crystal facet (1 0 1). The facet (1 0 1) was found polar which probably resulted in enhancement in the rate of dissolution and consequently the oral bioavailability of NSL-M. This outcome was also supported by surface chemistry determination from the morphology growth model and hirshfeld surface analysis. The research methodology used here is a step in the direction of a designed crystal habit modification, the scope of which can be extended to other molecules

Spherical Agglomeration of Platy Crystals: Curious Case of Etodolac

The present study reports an intriguing case study of agglomeration of platy crystals into spheroids. Etodolac a nonsteroidal anti-inflammatory drug is mainly used for rheumatoid arthritis, with emerging applications in management of prostate cancer and Alzheimer’s disease. It is a BCS class II drug with poor flow and compressibility issues. Recrystallization using various solvents resulted in platy crystals. Different polymers like hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and polyvinylpyrrolidone (PVP), and copolymers poly­(ethylene glycol) (PEG 400), poly­(vinyl alcohol) (PVA), and Poloxamer were explored at various concentrations and in different combinations to provide systematic inputs for the development of spherical agglomerates with optimal sphericity, dissolution, yield, and mechanical properties suitable for direct compression. Effects of different process parameters on agglomeration were studied. Agglomerates obtained were characterized using SEM, DSC, and P-XRD and were evaluated for enhancements in flow, compressibility, and dissolution. All the agglomerates have shown improved flow properties and compressibility. Unlike plain drug, all spherical agglomerates have shown acceptable plastic behavior during compression studies resulting in tablets at low pressures. Agglomerates developed using a unique combination of HPMC, HPC, and PEG has shown 94% drug release in 15 min. The recrystallized spherical agglomerates can be used as readily compressible material for continuous manufacturing

Ionic, Neutral, and Hybrid Acid–Base Crystalline Adducts of Lamotrigine with Improved Pharmaceutical Performance

Lamotrigine (L) is a known drug in the treatment of epilepsy and bipolar disorder. Due to its unique structure and functionalities, L is able to form both salts and cocrystals. The present study reports ionic, neutral, and hybrid crystalline forms of L with improved material properties and modified drug release rates. Novel forms of L with cinnamic acid (CA), ferulic acid (FRA), salicylic acid (SAC), and vanillin (VN) were successfully prepared and characterized using single crystal XRD, SEM, FT–IR, DSC, TGA, and powder XRD. LCA and LVN crystallized in <i>P</i>2₁/<i>c</i> space group, whereas LSAC crystallized in <i>P</i>1̅ space group. Pseudo-quadruple hydrogen bond with R₄² (16) graph set notation were observed in all three crystal structures of L. The characteristic FT–IR stretching peaks at 3326.53, 3341.53, and 3340.65 cm^–1 corresponding to N⁺–H bond were observed in LCA, LFRA, and LSAC. Comparison of dissolution profiles using similarity factor (f2) analysis revealed that the dissolution profiles of LCA, LFRA, and LVN were significantly different from that of L. LVN exhibited improved dissolution rate compared to L and LCA revealed a sustained release profile. Both these properties are important in designing oral dosage forms for neuropathic pain and bipolar disorder therapy. Further, LCA can be used in the development of extended release drug delivery systems for treating epileptic disorders

Ionic, Neutral, and Hybrid Acid–Base Crystalline Adducts of Lamotrigine with Improved Pharmaceutical Performance

Lamotrigine (L) is a known drug in the treatment of epilepsy and bipolar disorder. Due to its unique structure and functionalities, L is able to form both salts and cocrystals. The present study reports ionic, neutral, and hybrid crystalline forms of L with improved material properties and modified drug release rates. Novel forms of L with cinnamic acid (CA), ferulic acid (FRA), salicylic acid (SAC), and vanillin (VN) were successfully prepared and characterized using single crystal XRD, SEM, FT–IR, DSC, TGA, and powder XRD. LCA and LVN crystallized in <i>P</i>2₁/<i>c</i> space group, whereas LSAC crystallized in <i>P</i>1̅ space group. Pseudo-quadruple hydrogen bond with R₄² (16) graph set notation were observed in all three crystal structures of L. The characteristic FT–IR stretching peaks at 3326.53, 3341.53, and 3340.65 cm^–1 corresponding to N⁺–H bond were observed in LCA, LFRA, and LSAC. Comparison of dissolution profiles using similarity factor (f2) analysis revealed that the dissolution profiles of LCA, LFRA, and LVN were significantly different from that of L. LVN exhibited improved dissolution rate compared to L and LCA revealed a sustained release profile. Both these properties are important in designing oral dosage forms for neuropathic pain and bipolar disorder therapy. Further, LCA can be used in the development of extended release drug delivery systems for treating epileptic disorders

Syringic Acid: Structural Elucidation and Co-Crystallization

Syringic acid (SYRA) is a potential antioxidant used in traditional Chinese medicine and is an emerging nutraceutical. Current reports claim its potential anti-angiogenic, anti-glycating, anti-hyperglycaemic, neuroprotective, and memory-enhancing properties in various animal models. To date, SYRA crystal structure has not been elucidated, and no crystal engineering studies have been reported. This study reports the crystal structure of SYRA for the first time along with its nicotinamide (SNCT-E) and urea (SU-EA-M) co-crystals. All forms were successfully characterized using single crystal X-ray diffraction (XRD), powder XRD, and differential scanning calorimetry. Single crystal analysis revealed that SYRA crystallized in the <i>C</i>2/<i>c</i> space group, whereas SNCT-E (2:1) and SU-EA-M (1:2) crystallized in the <i>P</i>2₁/<i>n</i> and <i>Cmca</i> space group, respectively. Novel co-crystals have shown improved solubility, modified dissolution profiles, and improved flow and compressibility. Cytotoxic effects were explored in DU145 prostate cancer cell lines for the first time, and significant enhancement in cytotoxicity by the co-crystals was observed compared to plain components. A two-fold increase in % cytotoxicity of SNCT-E was observed when compared to the corresponding physical mixture. These studies shed light on potential utility of SYRA as a coformer for various pharmaceutical applications to design synergistic and organ-protective co-crystals

Hepatoprotective Cocrystals and Salts of Riluzole: Prediction, Synthesis, Solid State Characterization, and Evaluation

Riluzole is a drug, used to slow the course of amyotrophic lateral sclerosis. Due to its unique structure and functionalities, it is able to form both salts and cocrystals. This is a BCS class II drug with poor solubility and causes hepatotoxicity which limits its application. The present study aims toward development of novel solid forms of riluzole to address the said limitations. Apart from this, an attempt has been made to develop a prediction model using software tools to identify the appropriate synthons for formation of cocrystals. It was observed that out of 33 coformers selected, prediction results were in agreement with the experimental outcome for 25 coformers, which demonstrated the potential of the model developed. Seven new solid forms of riluzole, five cocrystals with ferulic acid, syringic acid, vanillic acid, cinnamic acid, and proline, and two salts with 2,4 dihydroxybenzoic acid and fumaric acid were successfully developed. All the solid forms were characterized by DSC, powder XRD, FTIR, and single crystal XRD. Single crystal X-ray analysis of the all solid form shows R₂²(8) motif between riluzole and coformers through N–H···O and O–H···N bond except riluzole-proline zwitterionic cocrystal. In riluzole-fumaric acid, partial proton transfer of O to N due to acidic H atom disorder has been observed. Dissolution profiles of all the solid forms were comparable to that of plain riluzole, and complete drug release was observed within 60 min for all systems. <i>In vivo</i> hepatotoxicity study with riluzole-ferulic acid and riluzole-syringic acid in mice model revealed its potential hepatoprotective effect to counterattack the hepatotoxic adverse effects of riluzole