Article pubs.acs.org/crystal
Effect of Rapid Pressurization on the Solubility of Small Organic Molecules Nathan T. Morgan,† Timothy C. Frank,‡ Russell J. Holmes,† and E. L. Cussler*,† †
Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota 55455, United States Engineering and Process Sciences, Core R&D, The Dow Chemical Company, Midland, Michigan 48674, United States
‡
S Supporting Information *
ABSTRACT: Crystallization under high pressure is an attractive approach to generate novel crystal polymorphs, solvates, and co-crystals of pharmaceuticals and other specialty chemicals. Here, we describe the effect of pressurization on the solubility of two common crystallization standards, paracetamol and piracetam. Simple theoretical models were developed to predict the change in solubility both due to pressurization and due to the temperature increase associated with adiabatic compression of the solution. These models were validated experimentally and provide a basis for experimental design. Interestingly, the decrease in solubility due to pressurization is often balanced by the increase in solubility from the temperature increase due to adiabatic compression of the solution.
1. INTRODUCTION
In order to explore thermodynamic properties at high pressure, two model pharmaceutical compounds were selected. Piracetam (2-(2-oxopyrrolidin-1-yl)acetamide), a nootropic drug, and paracetamol (N-(4-hydroxyphenyl)acetamide), a widely used analgesic, were chosen because of earlier studies in the high-pressure literature. Both compounds exhibit multiple polymorphs under ambient pressure and have solvates that appear only under high pressure.5,8 Additionally, piracetam has a polymorphic form which forms under high pressure,5 and paracetamol forms a co-crystal with piperazine at high pressure.9 The number of unique crystal systems recently reported for a variety of materials at high pressure suggests that a large number have yet to be discovered.3 Thermodynamic investigation of these model systems provides a background for future experiments.
Crystallization is an essential process in the manufacture of pharmaceuticals, agrochemicals, and other specialty chemicals. Careful control of polymorphic form is especially important in the pharmaceutical industry due to the varying processability and bioavailability of different polymorphs. This has led to efforts to identify and manufacture more desirable polymorphic forms of known bioactive materials.1,2 Recent work has shown that crystallization under high pressure can produce polymorphic forms not available or difficult to obtain through standard crystallization techniques.3,4 For example, Fabbiani et al. observed a new polymorph of piracetam predicted by computer simulation but inaccessible via traditional techniques.5−7 Crystallization at high pressure can also be used to generate novel solvates5,8 and co-crystals9 useful for a variety of applications. Most high-pressure crystallization is conducted in diamond anvil cells with sample volumes much less than 1 mL or more recently in large-volume hydraulic presses that have volumes around 3 mL.3,10,11 This is ideal for fundamental understanding and for screening materials, but it is not easily transferred to large-scale operation. Here, we describe an alternate approach to probe crystallization under high pressure that is scalable to industrially relevant quantities. This approach was used to determine the changes in solubility upon pressurization arising from both heating due to adiabatic compression and altered solubility with pressure. These two effects, which often have opposite influences on solubility, are frequently ignored at small scale and are not discussed in modern texts.12−14 © 2016 American Chemical Society
2. EXPERIMENTAL SECTION 2.1. Materials. Paracetamol (United States Pharmacopeia grade) and piracetam (≥98%) were obtained from Sigma-Aldrich Co. Hexane, methanol, acetone, toluene, and isopropanol were ACS grade. Ethanol was 200 proof United States Pharmacopeia grade. All materials were used as received without further purification. Water was deionized using a standard laboratory purification system and had a resistivity of 18.2 MΩ·cm. 2.2. Equipment. Crystallization experiments were conducted using a custom high-pressure reactor fabricated by the High Pressure Equipment Company. The reactor was of a piston and cylinder design Received: October 24, 2015 Revised: December 29, 2015 Published: February 1, 2016 1404
DOI: 10.1021/acs.cgd.5b01510 Cryst. Growth Des. 2016, 16, 1404−1408
Crystal Growth & Design
Article
as depicted in Figure 1. Pressure, applied on one side of the piston using a Teledyne ISCO 100DX high-pressure syringe pump with water
characteristic spike in temperature due to the heat of crystallization. This result was confirmed by visual observation. Melt densities of paracetamol and piracetam were measured using a simple volumetric technique. A Pyrex graduated cylinder was weighed and then packed with pure solid material. The cylinder was weighed again and sealed with a cork. The entire cylinder was then heated in a metal jacket to slightly above the material’s melting point and allowed to equilibrate. The melt volume was then read from the graduated cylinder.
3. RESULTS Crystallization at high pressure is a route to new polymorphic forms of pharmaceutical materials. This article explores the two major effects present when conducting crystallization experiments at high pressure: the change in solubility and the increase in solution temperature. These two effects were measured using the experimental techniques presented in Section 2 and will be justified with simple theoretical models in Section 4. 3.1. Temperature Changes Due to Pressurization. It is well-known that the adiabatic compression of a gas results in an increase of the gas temperature, but this effect is not often studied in liquids. Previous work has shown that this effect is typically small but measurable due to the comparatively incompressible nature of liquids under moderate pressure.15,16 At the high pressures required to obtain unique crystal structures, the temperature increase due to compression becomes significant. In fact, this phenomena is often observed during the high-pressure processing of food.17,18 During crystallization, adiabatic heating due to compression is especially important because even a small increase in solution temperature can lead to a dramatic increase in solubility. To accurately measure this effect, a variety of pure solvents were compressed rapidly (
