Improved method to determine and characterize the solubility of drugs in solid polymers.

摘要

Today in pharmaceutical industries, many drugs discovered are poorly soluble in water, and much research has been done to improve dissolution, apparent solubility and bioavailability of these drugs. One method to accomplish this is to formulate the drugs as solid solutions using several techniques such as spray dry, HME, rotavap, etc. However, due to high drug loading, this type of system becomes thermodynamically unstable and the drug will tend to aggregate and precipitate within a matrix during storage. There are many published models based solely on chemical arguments to determine the solubility of drug in polymer. Many of these studies are done at high temperatures, resulting in high drug solubilities that are above the solubility of the drug in the polymer. For these supersaturated solid solutions, the drug tends to precipitate from the solid solution during storage at room temperature, with a resulting loss of dissolution enhancement. The solubility of a drug in a solid polymer, which is the highest stable concentration of drug that can be dissolved in the polymer, is a relevant property because it represents the final state if such a dosage form is for a long time. However, this is difficult to measure at room temperature, in part because equilibration is very slow.;The goal of this project is to develop a new method, which includes chemical and heat content contribution from the solid environment to determine equilibrium solubility of drug in solid polymer, and evaluate the importance of the heat capacity effect in determining the solubility. The basis for the method is a thermodynamic model that gives the Gibbs energy change DeltaG ss resulting from forming a binary drug-polymer solid solution from the unmixed components, which includes contributions from heat capacity differences, breaking up of the solid drug structure, and drug-polymer mixing.;To achieve this, a method is proposed for calculating the solubility of a drug in a polymer at room temperature, by constructing change in Gibbs energy with respect to drug loading denoted by DeltaGss /w1 vs. n1/w1, where the minimum of the plot is determined. The method is based on a new thermodynamic model, and methods to obtain parameter values for the equation were also proposed and evaluated. To study this, Indomethacin and Griseofulvin were used as model drugs, and PVP K29/32, Eudragit L100 and Eudragit E100 were used as polymers for the study. In addition, an alternative annealing methods to the melting point depression is also developed and evaluates for determining solubility at various high temperature with same drug and polymer. Formulations that were developed were characterized using modulated Differential Scanning Calorimetry (DSC) and the required data were collected for both models.;The proposed method was compared with the published melting point depression method and the solubility parameter approach using the Flory-Huggins theory. From the newly developed Gibbs free energy model, it was concluded that a practical method was developed and tested to determine the maximum stable drug loading in polymer matrix. This can be useful when designing formulations because the model is based on the physical model that provides thermodynamics equation that can be used to evaluate the chemical potential of the drug in the solid solution as a function of the drug, polymer and drug loading. This is beneficial for several reasons. 1) Knowing of the solubility of the drug in a polymer gives us the maximum stable drug loading in the solid solution formulation. 2) Knowledge of the chemical potential would quantitatively give the thermodynamic degree of instability in formulation with high drug loading. 3) Knowledge of the chemical potential might be useful in developing approaches for the prediction of the dissolution enhancement of the drug resulting from the formulation in a solid solution.;From the annealing model results, it was concluded that the solubility was successfully measured at elevated annealing temperatures, and suggests that when there is less difference in the glass transition temperature Tg between drug and polymer or if drug acts as a plasticized, the mixture is more miscible above the glass transition temperature. Based on that result, it will be helpful to select a suitable drug-polymer combination and a storage condition to improve the stability of the system.;It is anticipated that the results obtained from both the models will be helpful for the further development of an in silico methods, compatible with this model and allow us to predicts matching of drug and polymers to optimize dosage form design and other formulation parameters before performing dissolution experiments.