Formation Kinetics and Stability of Carbamazepine−Nicotinamide Cocrystals Prepared by Mechanical Activation

Abstract

Co-milling of various carbamazepine (CBZ) polymorphic forms (form I, III and dihydate) with nicotinamide (NIC) was performed in this study to investigate the formation kinetics of carbamazepine−nicotinamide cocrystals (CBZ−NIC) and to evaluate their physical stability. Milling was carried out at room temperature using an oscillatory ball mill at a 1:1 molar ratio of CBZ and NIC for various times up to 60 min. A freshly prepared sample was used for each milling. In the stability study, the milled samples (4, 10, 15, and 30 min) were stored under four conditions (20 and 40 °C; 33 and 75%RH) for up to four weeks. Samples were analyzed by X-ray powder diffraction (XRPD) and differential scanning calorimetry. XRPD showed that all CBZ forms used in this study formed cocrystals when co-milled with NIC (characteristic XRPD peaks at 6.6, 8.9, 10.1, 20.4, and 26.5 °2θ). Cocrystal formation was qualitatively found to be fastest for CBZ dihydrate (CBZ DH, ∼1 min), followed by CBZ form I (∼6 min), and CBZ form III (∼15 min). Upon storage, cocrystals formed from CBZ DH were found to be physically stable under all conditions studied, regardless of a small amount of impurity. For the two anhydrous forms (CBZ I and III), the physical stability of the co-milled CBZ−NIC samples was dependent on the duration of milling, the relative humidity, and temperature of the storage conditions. Under “mild” storage conditions (i.e., 20 °C/33%RH), either partially or fully formed CBZ−NIC cocrystals were found to revert back to pure CBZ and NIC. Under “moderate” storage conditions (i.e., 20 °C/75%RH and 40 °C/33%RH), CBZ−NIC cocrystals reverting to pure CBZ and NIC would occur initially, followed by cocrystal formation with increasing storage time. On the other hand, “stress” storage conditions (i.e., 40 °C/75%RH) were found to be ideal for cocrystal formation and stability. Moisture has been found to favor cocrystallization. Water molecules appear to have a significant effect on the formation (water molecules from CBZ DH) and the stability (high humidity) of the CBZ−NIC cocrystal. The “purity” of the cocrystal samples (i.e., presence of CBZ and/or NIC seeds) can affect the physical stability of CBZ−NIC cocrystals prepared by mechanical activation.

Physico-mechanical and Stability Evaluation of Carbamazepine Cocrystal with Nicotinamide

“…An equimolar ratio of CBZ (1.181 g, 0.005 mol) and NCT (0.611 g, 0.005 mol) was co-ground in the cryomill (SPEX SamplePrep 6770 Freezer/Mill®, SPEX CertiPrep, Metuchen, NJ, USA) with a polycarbonate vial and stainless steel rod, which acted as an impactor for grinding (18). Liquid nitrogen was used as coolant for the mill.…”

“…Nicotinamide has been utilized as a coformer for the cocrystallization of celecoxib (15), theophylline (16), ibuprofen (17), CBZ (18,19), and lamotrigine (20). Reported methods of cocrystal preparation are solution cooling crystallization (21), ambient co-milling (18), cryogenic co-grinding (22), melting (23), and solvent evaporation (24).…”

“…Although CBZ and nicotinamide (NCT) cocrystals have been reported in the literature (18,19), there is a dearth of published information regarding their physicochemical, mechanical, and stability properties. Thus, it is important to evaluate these properties prior to product development in order to select an appropriate dosage form.…”

Characterization and Quality Control of Pharmaceutical Cocrystals

“…96) Solvent addition enables a much faster cocrystal formation than neat grinding while controlling crystal form and particle size. 97) These solvent effects result from the API and coformer dissolution on the solid surface. The speed of cocrystal formation increases with the grinding force.…”

Art of Synthesis of Desired Polymorphs: A Review

“…This technique involves decreasing the particle size of the compound using a grinder. The amorphous form of ranitidine has been obtained by grinding or cryomilling [32].…”