Interest of molecular/crystalline dispersions for the determination of solubility curves of drugs into polymers

Abstract

We present here a method to increase the dissolution rate of drugs into polymers in order to make easier and faster the determination of the solubility curves of these mixtures. The idea is to prepare molecular/crystalline dispersions (MCD) where the drug is dispersed into the polymer, partly at the molecular level and partly in the form of small crystallites. We show that this particular microstructure greatly increases the dissolution rate of crystallites since: (1) The molecular dispersion has a plasticizing effect which greatly increases the molecular mobility in the amorphous matrix. (2) The fine crystallite dispersion in the matrix strongly reduces the distances over which the drug molecules have to diffuse to invade homogeneously the polymer by dissolution. MCD are here obtained by combining solid-state co-amorphization by high energy mechanical milling and then recrystallization by annealing under a plasticizing atmosphere. We have used MCD to determine the solubility lines of the two polymorphic forms (I and II) of sulindac into PVP. The investigations have been performed mainly by DSC and powder x-ray diffraction.

Analytical and Computational Methods for the Determination of Drug-Polymer Solubility and Miscibility

“…The generated ASD was subjected to annealing at a temperature well above the T g of system and below the melting point of a drug for a specified time. The annealed ASD was then analyzed for T g , where the amount of drug present as molecularly dispersed ASD was retrieved using the T g -composition diagram as specified in the previous section. ,, This method provides a value of solubility at temperatures well below the melting point of the drug. , The solubility values obtained at different annealing temperatures can then be modeled using the FH equation to obtain X drug‑poly at the annealing temperature.…”

“…104,110,156 This method provides a value of solubility at temperatures well below the melting point of the drug. 157,158 The solubility values obtained at different annealing temperatures can then be modeled using the FH equation to obtain X drug-poly at the annealing temperature.…”

Contribution of low-frequency Raman spectroscopy to determine the solubility curves of drugs in polymers: The case of paracetamol/PVP

“…Crystalline Paracetamol (C8 H9 NO2) was provided by SIGMA ALDRICH ® and used without any further purification. Amorphous PVP K12 PF (Mw = 2000-3000 g.mol -1 , 5% w/w moisture) was kindly provided by BASF and was used without any further purification Molecular / Crystalline Dispersions (MCD) of paracetamol and PVP were produced using a two-stage protocol which was previously described in details in reference 20 . During the first stage, a physical mixture paracetamol / PVP [85:15] was cryo-milled during 1 hour.…”

“…Reaching equilibrium saturated states thus becomes increasingly difficult on approaching the glass transition temperature (Tg) of the polymer and appears to be impossible, in practice, below Tg. Recently, Latreche et al 20 have shown that much faster dissolution rates could be obtained by using Molecular and Crystalline Dispersions (MCD) instead of physical mixtures. MCD can be easily obtained, directly in the solid state, in two steps.…”

“…In this paper, we show how to use LFRS (Low-Frequency Raman Spectroscopy) to determine the solubility line of a drug in a polymer during the heating of a MCD of the two components. A special attention will be given to the capability of LFRS to directly determine the fraction of drug dissolved inside the polymer 20 , allowing a direct and fast determination of the solubility line in the course of a single heating experiment. The demonstration will be performed with the paracetamol / PVP binary mixture.…”