N. Jagadeesh Babu

Nitrofurantoin–p-aminobenzoic acid cocrystal: Hydration stability and dissolution rate studies

Nitrofurantoin (NF) drug is known to transform to a hydrate form in aqueous medium. The hydration stability and dissolution rate of a few cocrystals of NF were compared with that of its stable β polymorph and hydrate form II. Hydrogen bonding and molecular packing in the novel cocrystal structures were analyzed. Pharmaceutical cocrystals of NF with p-aminobenzoic acid (PABA) and urea showed superior physicochemical properties compared with the known L-arginine salt hydrate. All the solid-state adducts were characterized by single-crystal X-ray diffraction, X-ray powder diffraction, differential scanning calorimetry, and thermogravimetric analysis. NF-PABA cocrystal was found to be superior among the compounds studied in terms of minimal transformation to NF hydrate and comparable dissolution rate to the reference drug.

Crystal engineering of stable temozolomide cocrystals.

The antitumor prodrug temozolomide (TMZ) decomposes in aqueous medium of pH≥7 but is relatively stable under acidic conditions. Pure TMZ is obtained as a white powder but turns pink and then brown, which is indicative of chemical degradation. Pharmaceutical cocrystals of TMZ were engineered with safe coformers such as oxalic acid, succinic acid, salicylic acid, d,l-malic acid, and d,l-tartaric acid, to stabilize the drug as a cocrystal. All cocrystals were characterized by powder X-ray diffraction (PXRD), single crystal X-ray diffraction, and FT-IR as well as FT-Raman spectroscopy. Temozolomide cocrystals with organic acids (pK(a) 2-6) were found to be more stable than the reference drug under physiological conditions. The half-life (T(1/2)) of TMZ-oxalic and TMZ-salicylic acid measured by UV/Vis spectroscopy in pH 7 buffer is two times longer than that of TMZ (3.5 h and 3.6 h vs. 1.7 h); TMZ-succinic acid, TMZ-tartaric acid, and TMZ-malic acid also exhibited a longer half-life (2.3, 2.5, and 2.8 h, respectively). Stability studies at 40 °C and 75 % relative humidity (ICH conditions) showed that hydrolytic degradation of temozolomide in the solid state started after one week, as determined by PXRD, whereas its cocrystals with succinic acid and oxalic acid were intact at 28 weeks, thus confirming the greater stability of cocrystals compared to the reference drug. The intrinsic dissolution rate (IDR) profile of TMZ-oxalic acid and TMZ-succinic acid cocrystals in buffer of pH 7 is comparable to that of temozolomide. Among the temozolomide cocrystals examined, those with succinic acid and oxalic acid exhibited both an improved stability and a comparable dissolution rate to the reference drug.

High Z′ polymorphs have shorter C–H⋯O interactions and O–H⋯O hydrogen bonds

The higher Z′ polymorph has a shorter C–H⋯O interaction in 26 out of 38 crystal structures with two or more forms; these data suggest the dominance of stronger hydrogen bonds, or enthalpy, in the crystallization of multiple Z′ crystal structures.

Temozolomide hydrochloride dihydrate

The X-ray crystal structure of temozolomide hydrochloride shows that the dihydrate salt contains one neutral temozolomide, one temozolomide-H+Cl−, one H3O+·Cl−, and three water molecules. This is the first crystallographic evidence of a protonated form of the antitumour drug temozolomide. The protonation of water O and imidazole N of the drug are rationalized by calculated pKas.

Water mediated tube in tetrapeptide cyclo(Phe-Pro-Leu-Aha) trihydrate and crystal structure of cyclo(D-Phe-Pro-Leu-Aha) anhydrate

Water molecules connect 6.5 × 4.5 A diameter rings in the X-ray crystal structure of 16-member tetrapeptide cyclo(Phe-Pro-Leu-Aha) (1) trihydrate. However, stereoisomer cyclo(D-Phe-Pro-Leu-Aha) (2) crystallized in anhydrate form. Structural differences in L- to D-amino acid exchanged cyclic peptides are analyzed.