Understanding Polymer Properties Important for Crystal Growth Inhibition—Impact of Chemically Diverse Polymers on Solution Crystal Growth of Ritonavir

Abstract

The use of supersaturating dosage forms, such amorphous dispersions, is an increasingly common approach for improving delivery of poorly water-soluble drugs. Crystallization must be prevented to maintain supersaturation, and so, the presence of an effective crystal growth inhibitor in solution is desirable to prolong supersaturation. In this study, the effectiveness of a group of chemically diverse polymers, including a number of novel cellulose derivatives, at inhibiting the crystal growth of ritonavir from solution was quantified, enabling key polymer properties important for crystal growth inhibition of ritonavir to be elucidated. In general, the greater effectiveness of the cellulose derivatives relative to the synthetic polymers was ascribed to a moderate level of hydrophobicity, the semirigid structure of the cellulose polymers, and their amphiphilicity. Interestingly, some of the novel cellulose polymers were found to be more effective crystal growth inhibitors than commercially available cellulose derivatives. Orthogonal partial least-squares analysis further pointed to the importance of polymer hydrophobicity. These properties of the cellulose-based polymers are likely to promote adsorption onto the crystallizing drug surface. Given the diversity of impact of polymers on crystal growth inhibition, it is clearly important to consider this factor when choosing a polymer for a supersaturating dosage form.

Physicochemical characterization and pharmacological evaluation of ezetimibe-PVP K30 solid dispersions in hyperlipidemic rats

“…However, unstable supersaturated drug precipitates from the solution in order to reach equilibrium state [46]. During drug precipitation, adsorption of polymer on the particles surface can prevent crystal growth by blocking active surfaces and providing steric stabilization [47]. Moreover, hydrogen bonding between the drugs and polymers may help to the maintenance of supersaturation state [48].…”

Impact of Solubilizing Additives on Supersaturation and Membrane Transport of Drugs

“…Additives such as polymers at low solution concentrations do not generally enhance equilibrium crystalline solubility of small molecules (28). Rather, they inhibit nucleation (5,(29)(30)(31)(32), and/or crystal growth (33)(34)(35)(36) and thereby stabilize supersaturated solutions (29). In contrast, the other additives such as surfactants or complexing agents typically increase equilibrium solubility.…”

A study on the effect of the polymeric additive HPMC on morphology and polymorphism of ortho-aminobenzoic acid crystals

“…Similar studies were conducted by Alonzo et al (2012) and Oucherif et al (2013) who analysed and modelled the growth and nucleation kinetics of felopidine in the presence of HPMC [33], [34]. The same research group also used HPMC to nucleate amorphous flutamide [14] and several other polymeric additives to inhibit growth of ritonavir [35][36][37]. In some cases polymers can promote growth: in particular, it was found that a very small amount of ethylene dinitrotetraacetic acid disodium salt (EDTA) could accelerate the growth of potassium dihydrogen phosphate (KDP) crystals by forming molecular complexes with adventitious impurities in solution and eliminating their inhibiting effect [38].…”