(200aa) Nucleation Kinetics of Pharmaceutical Co-Crystals

Nucleation Kinetics of Pharmaceutical Co-crystals

Hannah McTague

Abstract

Approximately 40% of all drug molecules on the market are suffering from physio-chemical property (PCP) problems such as low solubility and dissolution rates, poor thermal stability and bioavailability. These properties can be largely attributed to the molecular arrangement and intermolecular forces within the solid material. The formation of co-crystals consisting of an API with a co-former or two APIs can offer a solution by allowing one to modify the PCPs without changing the chemical properties of the drug molecule.

Although there have been many studies on co-crystals, little work has been done regarding the nucleation and growth kinetics of pharmaceutical co-crystals.

The theophylline:salicylic acid (THP:SA) co-crystal has been synthesized and exists as a 1:1 co-crystal. THP:SA co-crystal exhibits favourable properties in the solvent chloroform wherein the system dissolves congruently in the same 1:1 stoichiometric ratio. The solid co-crystal was characterised according to PXRD, Single Crystal XRD, TGA and DSC and compared with the properties of each individual coformer. The solubility of the co-crystal and each individual component has also been identified.

As a method of studying the nucleation kinetics of THP:SA induction time measurements have been undertaken. These experiments have initially been performed at 6 different concentrations allowing for a gradient of supersaturation ratios to exist. In order to measure the induction times the following protocol has been followed: 500ml of solution at the desired concentration is created. Upon 24 hour equilibration at a chosen dissolution temperature, which is 5°C above the saturation temperature, the solution is filtered into 20ml aliquots in pre-heated vials and allowed to equilibrate at dissolution temperature. The vials can then be simultaneously submerged at a fixed nucleation temperature of 10°C and recorded by a HD video recorder. Following nucleation the video is analysed by eye and the moment of first detectable crystals is recorded for each vial. 40-80 vials are recorded for each concentration. These results provide a median induction time, where the induction time is defined as the time period between the moment the vials are submerged at nucleation temperature and crystals are detected.

A probability distribution has been created displaying these results in which the median induction times can be seen to be representative of the driving forces present. On the distribution it is obvious that at the same concentrations there exists large variation in induction times. This is attributed to the stochastic nature of nucleation at small volumes which holds valuable information regarding the crystal nucleation rate. A set of induction times under equal supersaturation and temperature results in the crystal nucleation rate (J).

In order to analyse according to classical nucleation theory the median induction times have been used to identify the kinetic and thermodynamic parameters A and B allowing for the subsequent calculation of interfacial energy. B is seen to have a value of 3202766.31 s/K^-3, which represents the dimensionless energy barrier for nucleation. A is found to have a value of 32.51 m^-3s^-1 and this describes the molecular kinetics of the nucleation process i.e. it reflects how building units attach to the nucleus.

Using the obtained values of the thermodynamic parameter B the value of the interfacial energy γ can be calculated by assuming spherical nuclei and using the corresponding shape factor. The molecular volume for the THP:SA co-crystal was obtained from the CSD file. The interfacial energy for the co-crystal has been found to be 1.62 mJ/m².

The same experiments have been performed on the individual components namely theophylline and salicylic acid revealing interfacial energies of 0.85 mJ/m² and 0.71 mJ/m² respectively.

The calculated interfacial energies can be compared with that of the THP:SA co-crystal and analysed such as to examine how the nucleation kinetics of the API may be altered due to the formation of a co-crystal. Based on the current results there is an indication that due to the higher interfacial energy value of the co-crystal, versus both of the individual components, the co-crystal is harder to nucleate at these small volumes.