Characterizing the Impact of Hydroxypropylmethyl Cellulose on the Growth and Nucleation Kinetics of Felodipine from Supersaturated Solutions

Abstract

The use of amorphous drugs to generate supersaturated solutions that have the potential to enhance oral drug delivery is currently an area of intense interest. From an in vivo performance standpoint, inhibiting crystallization from these supersaturated systems is extremely important. In this study the ability of a polymer, hydroxypropylmethyl cellulose (HPMC), to inhibit nucleation and crystal growth of felodipine from supersaturated solutions was investigated. Nucleation and bulk crystal growth rates, in the absence and presence of seed crystals, were estimated from de-supersaturation curves. It was found that the presence of ppm levels of predissolved HPMC could inhibit both nucleation and growth of felodipine crystals. Empirical and mechanistic models were used to quantify the magnitude of inhibition. Crystal growth shifted toward an integration-controlled mechanism in the presence of HPMC where the overall impact on the growth rate was found to be strongly dependent on the extent of supersaturation. As predicted by theory, the polymer became less effective as a growth inhibitor with increases in supersaturation. The nucleation rate at similar supersaturations was significantly reduced in the presence of HPMC. A direct comparison of the impact of HPMC on nucleation and growth demonstrated that delaying nucleation was much more crucial to the stabilization of a supersaturated solution than hindering crystal growth.

Impact of Solubilizing Additives on Supersaturation and Membrane Transport of Drugs

“…Use of enabling formulations frequently improves oral drug absorption for systems with solubility-limited bioavailability (1)(2)(3). Amorphous solid dispersions (ASD), where the higher apparent solubility and dissolution rates of amorphous solids lead to supersaturated solutions (4,5) are a common formulation approach. Lipid based drug delivery systems (6), salts and weak bases (7) may also result in the formation of supersaturated solutions in vivo.…”

“…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.…”

Thermal Processing of PVP- and HPMC-Based Amorphous Solid Dispersions

“…As these are typically metastable systems, maintaining physical stability by preventing recrystallization is crucial. Polymers are extremely effective when used to prevent recrystallization (9)(10)(11)(12); however, the manufacturing process used may limit the range of polymers that can be utilized. In this study, it was hypothesized that the formulation design space could be increased by using KinetiSol® Dispersing (KSD) as opposed to hot-melt extrusion (HME) for the manufacture of amorphous solid dispersions (ASD), mainly with regard to polymers of increasing molecular weight.…”

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

“…Vetter et al (2011) used the surfactant Pluronic F127 to slow down the growth of ibuprofen [32]. 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].…”