Sudhir Mittapalli

Celecoxib cocrystal polymorphs with cyclic amides: synthons of a sulfonamide drug with carboxamide coformers

The trimorphic cocrystals of celecoxib with δ-valerolactam contain sulfonamide dimers and catemers together with carboxamide dimers, whereas the caprolactam cocrystal is sustained by a SO2N–H⋯H–NOC heterosynthon. The alternation of synthons with even–odd ring coformers offers a crystal engineering approach to sulfonamide–carboxamide cocrystals.

Modularity and three-dimensional isostructurality of novel synthons in sulfonamide–lactam cocrystals

Novel supramolecular synthons for primary sulfonamides with cyclic amides (GRAS coformers) are introduced for the crystal engineering of pharmaceutical cocrystals of sulfa drugs. The cocrystals of this model study exhibit isostructurality and isosynthons mediated by SO2NH2⋯CONH hydrogen bonding.

Can we exchange water in a hydrate structure: a case study of etoricoxib

Novel crystalline forms of etoricoxib (ETR) with pharmaceutically acceptable coformers (generally regarded as safe, GRAS), such as glutaric acid (1:1), adipic acid (2:1), suberic acid (1:1), and caprolactam, were co-crystallized. The solid forms were prepared from ETR hemihydrate form I and characterized by powder XRD, DSC, and IR, and finally confirmed by single crystal X-ray diffraction. The exchange of water with an organic acid coformer in the crystal structure is explained by lattice energy calculations.

Mechanochemical synthesis of N-salicylidene­aniline: thermosalient effect of polymorphic crystals

Among the halogen derivatives of N-salicylideneaniline, polymorphs of the dichloro compound A showed the mechanical response of jumping (Forms I and III) and sudden blasting (Form II) upon heating. This difference is ascribed to the layered packing in Forms I and III such that the thermal stress acts in a unidirectional manner while for the corrugated layer structure of Form II the outcome is blasting because the thermal energy dissipates in different directions.

Rufinamide: Crystal structure elucidation and solid state characterization

Graphical abstract Figure. No caption available. HighlightsSingle crystals of rufinamide grown in dimethylformamide (R‐DMF) crystallized in triclinic form with P‐1 space group.Solid state characterization of R‐DMF were performed using analytical tools like DSC, PXRD, TGA and FTIR.Solubility and dissolution of R‐DMF in presence of different media was conducted.Assessment of flow and compressibility behavior of R‐DMF revealed poor flow and elastic behavior.Drug‐ excipient compatibility was determined by thermal analysis. ABSTRACT Rufinamide (R) is a triazole derivative approved for the management of partial seizures and seizures associated with Lennox‐Gastaut Syndrome, in November 2007. Crystal structure, solid state characterization, drug‐excipient compatibility and solubility play a pivotal role in formulation development. This work deals with the crystal structure elucidation of R by single crystal X‐ray diffraction and solid state characterization by thermal, spectroscopic and crystallographic techniques. Drug‐ excipient compatibility was assessed by differential scanning calorimetry (DSC). New RP‐HPLC method for quantification of R was developed with improved retention time. Solubility and dissolution of drug in different media was determined. Additionally, the flow behavior of the drug was evaluated by measuring Carrs index and Hausners ratio, while the compressibility behavior was studied using Wells protocol. R crystallized from dimethylformamide (R‐DMF) was utilized for single crystal analysis. The drug crystallized in triclinic crystal system with P‐1 space group. Asymmetric unit cell consists of two molecules of R held by intermolecular hydrogen bond (connected by N—H…O, which forms the catemeric chain). Analytical outcomes from DSC, thermogravimetric analysis (TGA) and powder X‐ray diffraction (PXRD) revealed that the drug was present in pure crystalline form and was devoid of any polymorphic or pseudopolymorphic impurities. Influence of pH on the solubility and dissolution of R‐DMF was found to be insignificant. The drug exhibited poor aqueous solubility, which was improved nearly 4.6 fold with the addition of 2% sodium lauryl sulphate (SLS). The drug exhibits poor flow and elastic compression nature. Excipients such as poly ethylene glycol (PEG) 8000, SLS, lactose monohydrate, starch and Hydroxypropyl methylcellulose (HPMC) E15 were incompatible with R‐DMF as identified by thermal analysis. It is envisaged that these information regarding solid state properties of R‐DMF would aid in identifying a logical path for formulation development.

Thermomechanical effect in molecular crystals: the role of halogen-bonding interactions

Among the halogen derivatives of salinazid, the chloro and bromo analogues show a mechanical response of jumping and breaking upon heating. Such a thermosalient response is ascribed to the sudden release of accumulated strain during the phase transition and to anisotropy in the cell parameters.

Thermomechanical effect of molecular crystals and role of halogen bonding

The design and synthesis of mechanically responsive materials are fascinating and these types of materials are potential candidates for developing materials which will convert thermal energy to mechanical work. In the present investigation for the first time, we reported the thermosalient effect in a series of halo derivatives, the halo derivative with higher electronegativity and poor halogen bond strength (Cl···Cl) shown good thermal response and the decrease in effect were observed with decrease in electronegativity and increase in halogen bond strength (I···I).1 We observed the different thermal events (jumping/explosion, and cracking) in halogen derivatives such as Compound-A (3,5-di Chloro Salicylidene), B (3-Bromo-5-Chloro Salicylidene), C (3,5-di Bromo Salicylidene) and D (3,5-di Iodo Salicylidene) in a decreasing order even they all are isomorphous, 3D isostructural and having the same type of hydrogen/halogen bonding interactions and similar packing, except the change in halogen atom. The Compound-A exists in three polymorphic Forms, two room temperature (Form I and II) and one high-temperature Form (Form III) where Form I to III is a reversible thermosalient transition and From II to III is irreversible and non-thermosalient. Compound-B and C also exist in two polymorphic Forms; Compound-B Form I to II is irreversible whereas Compound-C is reversible with thermosalient effect. The thermosalient behavior of molecular crystals is mainly due to anisotropy in the cell parameters (increase in a-axis and decrease in b, c-axes) and sudden release of accumulated strain during phase transition.2 This study demonstrates the utility of halogen and hydrogen bonded molecular crystals in exhibiting thermosalient effect under thermal stress and also presents a rationale for the design of thermo-responsive crystals and energy converting materials. [1] Desiraju, G. R. & Parthasarathy, R. J. (1989). J. Am. Chem. Soc. 111, 8725-8726. [2] Etter, M. C. & Siedle, A. R. (1983). J. Am. Chem. Soc. 105, 641–643. [3] Mittapalli, S., Perumalla, D. S. K. & Nangia, A. (2017). (Manuscript in Press)