Amphiphilic Block Copolymer as a Crystal Habit Modifier

Abstract

The purpose of this study is to evaluate amphiphilic block copolymers, a new class of additives, for the habit modification of pharmaceuticals. The additive chosen is poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA). The model compound chosen is tolazamide, an oral hypoglycemic pharmaceutical agent. Crystallization was carried out in aqueous media by pH adjustment, with or without additives. PEG-b-PLA was found to be very effective in modifying the crystal habit of tolazamide. The habit changed from a needle shape to a plate shape at a concentration of 12.5 μg/mL. This change in habit required both blocks and could not be achieved in the presence of either block alone. A small amount of copolymer (0.55% weight) was found on/in tolazamide particles crystallized in the presence of 30 μg/mL of copolymer. Washing the crystals with toluene effectively removed the copolymer. It is thus concluded that the block copolymer is mainly adsorbed on the crystal surface(s) rather than being incorporated into the lattice of tolazamide crystals. The recrystallized tolazamide is of the same crystal form as that of the original solid, regardless of the concentration of the copolymer used.

Crystal Morphology Engineering of Pharmaceutical Solids: Tabletting Performance Enhancement

“…Control of crystal morphology can be achieved by solvent selection (9)(10)(11)(12) and/or tailor-made additives (13)(14)(15). In the context of pharmaceutical solids, the solvent-induced crystal habit modification approach is limited by the solvent toxicity and cost, crystallization efficiency, and the purity requirements of the final product.…”

Modification of Drug Crystallization by Cyclodextrins in Pre-formulation Study

“…Therefore we usually obtain the most stable polymorph at experimental conditions and it is difficult to isolate the intermediate metastable crystals appearing in earlier steps of crystallization. Recently, advanced approaches that selectively modify the crystallization behavior of drugs by adding tailor-made additives such as compounds having similar structure, 20,21) surfactants, [22][23][24] and polymers [25][26][27] have been reported. However, such tailor-made additives are likely to incorporate into the crystal lattice of drugs due to their structural similarities, 28) which is particularly caused when using low-molecular weight additives.…”

Drug–polymer Interactions at Water–Crystal Interfaces and Implications for Crystallization Inhibition: Molecular Dynamics Simulations of Amphiphilic Block Copolymer Interactions with Tolazamide Crystals

“…Polymers are also used to maintain supersaturation during dissolution of enabling formulations for maximizing formulation performance . Finally, polymers can play an important role in modifying the crystal habit during solution crystallization …”

“…The model system chosen for this study comprised tolazamide (TLZ), an oral hypoglycemic agent, and poly(ethylene glycol)‐block‐poly(lactic acid) (PEG‐ b ‐PLA), an amphiphilic block copolymer based on the interesting work published by Kuldipkumar et al PEG‐ b ‐PLA was observed to change the TLZ crystal habit from needle to plate shape (shown in Fig. ).…”

“…Tolazamide crystals obtained (a) in the absence of PEG ‐ b ‐ PLA and (b) in the presence of 50 μg/mL of PEG ‐ b ‐ PLA . Adapted from Kuldipkumar et al to with permission.…”