Theoretical and Practical Approaches for Prediction of Drug–Polymer Miscibility and Solubility

Abstract

Purpose. Crystallization of drugs formulated in the amorphous form may lead to reduced apparent solubility, decreased rate of dissolution and bioavailability and compromise the physical integrity of the solid dosage form. The purpose of this work was to develop thermodynamic approaches, both practical and theoretical, that will yield a better understanding of which factors are most important for determining the ability of polymers to stabilize amorphous active pharmaceutical ingredients (API). Materials and Methods. Lattice based solution models were used to examine miscibility criteria in APIpolymer blends. Different methods were used to estimate the Flory<Huggins interaction parameter for model API-polymer systems consisting of felodipine or nifedipine with poly(vinylpyrrolidone) (PVP). These were melting point depression and determination of solubility parameters using group contribution theory. The temperature and enthalpy of fusion of crystalline API alone and the fusion temperature of the API in the presence of the polymer were measured by differential scanning calorimetry. The resultant thermal data were used to estimate the reduced driving force for crystallization and the solubility of the API in the polymer. Results. Flory<Huggins theory predicts that, for typical API-polymer systems, the entropy of mixing is always favorable and should be relatively constant. Due to the favorable entropy of mixing, miscibility can still be achieved in systems with a certain extent of unfavorable enthalpic interactions. For the model systems, interaction parameters derived from melting point depression were negative indicating that mixing was exothermic. Using these interaction parameters and Flory<Huggins theory, miscibility was predicted for all compositions, in agreement with experimental data. A model was developed to estimate the solubility of the API in the polymer. The estimated solubility of the model APIs in PVP is low suggesting that kinetic rather than thermodynamic stabilization plays a significant role in inhibiting crystallization.Conclusions. The thermodynamics of API-polymer systems can be modeled using solution based theories. Such models can contribute towards providing an understanding of the compatibility between API and polymer and the mechanisms of physical stabilization in such systems.

Physical stability of solid dispersions with respect to thermodynamic solubility of tadalafil in PVP-VA

“…4). Thus, thermal degradation of Td and PVP-VA, even at a heating rate of 10 °C/min, prevents the use of conventional methods for solubility assessment, which requires reliable measurements of the melting events of the drug [13,18,17]. …”

“…Solid dispersions are preferably amorphous systems where the drug substance is molecularly dispersed in an inherently amorphous polymer. The initial drug loading may be boundlessly high but from the thermodynamic point of view only the amount not exceeding its intrinsic solubility in a polymer does not tend to crystallize [13]. This gives an advantage over amorphous drugs without excipients, which are always high energy and therefore highly physically unstable structures.…”

“…This gives an advantage over amorphous drugs without excipients, which are always high energy and therefore highly physically unstable structures. Crystallization can be considered as a kinetically driven process depending on mobility of molecules but thermodynamic properties resulting from the drug content and its solubility in the polymer are thought to be the key parameters regarding physical stability of solid dispersions [13,15].…”

“…It is important as to date all described methods of solubility determination are based on measurements at temperatures above Tg of the polymer and one of the most common protocols known as "the melting point depression method" utilizes the decrease of the drug melting temperature in a physical mixture [13]. Apart from thermal degradation, the biggest drawback of this method is the risk of solubility underestimation caused by low molecular mobility in a viscous polymer and an inadequate shift of the endotherm.…”

Preparation and Characterization of Solid Dispersion of Modafinil Using Peg6000 as Hydrophilic Carrier for Improvement of Dissolution Profile

“…The basis for this interest stems from the increased rate of dissolution, which can range from hundreds to thousands fold increase, even for the most insoluble active pharmaceutical ingredients 3 . For drugs whose bioavailability is limited due to poor aqueous solubility (as in BSC class II drugs), the improvement in solubility may lead to enhanced bioavailability [8][9][10][11] . Solid dispersion represents a useful pharmaceutical technique for increasing the dissolution, absorption, and therapeutic efficacy of drugs in dosage forms [12][13] .…”