(44f) The Surface Properties of Organic Crystalline Solids and Their Interactions with Polymeric Excipients and Binders

The physiochemical properties of solid state pharmaceuticals are crucial in understanding drug manufacturing, processing, and biological absorbtion. They govern the flowability, dispersibility, bulk density, dustiness, compressibility, and particle aggregation of active pharmaceutical ingredients (APIs)¹. Binders and excipients are added to the formulation so as to achieve greater uniformity in the final product, and to enlarge the drug particles by agglomeration. Thus, particle design and characterozation are crucial for the understanding of the product being delivered to the consumer^2,3. Many advances have been made in this research but given there are many mechanisms that affect the final product, itâ??s difficult to model and predict what will occur accurately, such as adhesion, attrition, coalescence etc⁴.

In pharmaceutical processes micron and submicron sized particles are used. In this scale, surface properties such as surface free energy heavily influence particle behaviour⁵. Surface free energy, or more conveniently surface energy, is defined as the energy required to form a surface of a particular material per unit area, where various components make up the total surface energy for one specific facet of a crystal. By having a better understanding of these components and the surface energies, researchers can better predict the properties of drugs. This includes how particles form, grow, break, stick, flow, and more. This then offers more data for researchers to understand how the APIs interact with polymeric excipients and binders.

Current research and models have too often made assumptions disregarding the surface heterogeneity of the particles⁶. Due to the anisotropy of the crystal, the properties are vastly more complex than the simple assumptions of spherical homogeneous particles⁶. Measuring these differences is crucial in the further development of this field and drug formulation as a whole. The most appropriate way to measure the facet specific surface energies is by sessile drop contact angle measurements or inverse gas chromatography⁵. This can be expanded further to compare the energetic interactions of pharmaceuticals with solvated excipients and see how we may better predict the physiochemical properties of the resulting particles⁴.

Our study chooses to focus on the formulation of pharmaceuticals alongside polymers so as to offer a better understanding of their properties during such processes. This will offer better control in their manufacturing and later ties in to the drugs bio-availability. Our investigation is divided into two parts, the first involves property analyses of the crystals and powders of the API, and the second the interactions between the drugs and excipients. Here we chose to use both three polymorphs of anhydrous Carbamazepine and Copovidone as our model API and excipient respectively. Together, we offer further data to facilitate the modelling in the particle design of pharmaceuticals.

We performed studies on the polymorphs of anhydrous Carbamazepine using: sessile drop contact angle measurements (CA), finite dilution inverse gas chromatography analysis (FD-iGC), and X-ray photoelectron spectroscopy (XPS). The interactions between Copovidone and the main facets of P-Monoclinic Carbamazepine were analysed with two experiments. In the first, we measured the contact angle of Copovidone dissolved in water at various amounts, on the crystal facets of Carbamazepine. In the other we measured the contact angle of water on the crystals facets with spun cast Copovidone on them. The combination of these instruments helps elucidate and predict some of the surface properties that may affect drug formulation, offering more comprehensive data on their anisotropy.

P-Monoclinic seeds (with dimensions about 0.5 x 0.5 x 0.1 cm) were prepared by two step cooling crystallization of a supersaturated methanol solution. These seeds were suspended to grow in a, slowly evaporating, supersaturated methanol solution6¹. The crystals grew to sizes up to 5x3x3 cm, with three main facets exposed; (100), (002) and (010). CA measurements, using diiodomethane, water, formamide and ethylene glycol, were performed on these facets to determine their surface energy, both the Lifshitz-van der Waals and the acid-base components (using VOCG approach), and their affinity to water. The dispersive surface energy ranges from about 48 mJ/m² to 40 mJ/m² depending on the facet. The acid-base component has a smaller contribution, with its value going up to 10 mJ/m². However, there is large variation between the acid and the base component. The acidic component can be more than one order of magnitude larger than the basic one.

XPS analysis was conducted on the facets showing that strong amine presence on the surface of two of them. Contact angle measurements suggests that these two facets are the more hydrophilic. From the other hand the carbonyl component of the facets, less abundant than the amine one, does not seem to correlate with the water affinity.

P-Monoclinic Carbamazepine was recrystallized by stirring a supersaturated ethanol solution and the Triclinic polymorph was prepared by heating the P-Monoclinic polymorph at 160^oC overnight⁷. FD-IGC measurements were performed on the two polymorphs to determine their surface energy heterogeneity. It was found that the most stable Monoclinic polymorph is lower energetically than the Triclinic. Computational analysis of the surface energy map of the Monoclinic polymorph shows some agreement with the measured surface energies⁸.

We measured the contact angles of 0.1%, 0.25%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 10%, and 20% polymeric solutions by weight on three facets of P-Monoclinic Carbamazepine: (002), (010) and (100), to better understand how Copovidone interacts with facets of Carbamazepine. The amount of polymer in the solution was positively correlated to the solutions wettability on all three facets; the contact angle became smaller. Between the three facets the more apolar they were according to the FD-iGC, the more wettable they became as polymeric content increased. These increases were not identical, but were more pronounced as the dispersive component on the contact angle solution increased, i.e. as the polymeric content increased.

The data above was corroborated with water contact angle measurements of crystalline facets spun cast with Copovidone on top of them. This led to a mark increase in wettability, therefore the surface became more hydrophilic, in agreement with the data supplied in the previous paragraph. Della Volpe proposes that the acidic component of the surface energy of water is 6.5 times stronger than the basic one, from the other hand FD-IGC measurements on Copovidone reveal that it has a very strong basic component and a Lifsitz-Van der Waals component similar to that of Carbamazepine. Thus, it can be concluded that the increase in hydrophilicity is attributed to the acid-base interactions.

Previous studies have established the concept of anisotropy in pharmaceutical crystals. These anisotropic properties were proved to affect dry properties of pharmaceutical processes such as cohesion. However, this study goes beyond dry interactions revealing the importance of crystal anisotropy in solid-liquid interactions, particularly important in a wide range of pharmaceutical processes such as wet granulation, dissolution etc. It highlights the need for in depth understanding of crystal anisotropy in order to develop robust model predictive tools describing solid-liquid processes. Furthermore, it highlights the need for the application of complementary techniques to accurately describe crystal anisotropy and it also indicates the importance of computational models in these studies

References:

1. Ho, Raimundo, Majid Naderi, Jerry Y. Y. Heng, Daryl R. Williams, Frank Thielmann, Peter Bouza, Adam R. Keith, Greg Thiele, and Daniel J. Burnett. 2012. "Effect Of Milling On Particle Shape And Surface Energy Heterogeneity Of Needle-Shaped Crystals". Pharm Res 29 (10): 2806-2816.
2. Krycer, Ian, David G. Pope, and John A. Hersey. 1983. "An Evaluation Of Tablet Binding Agents Part I. Solution Binders". Powder Technology 34 (1): 39-51.
3. Simons, S.J.R., D. Rossetti, P. Pagliai, R. Ward, and S. Fitzpatrick. 2005. "The Relationship Between Surface Properties And Binder Performance In Granulation". Chemical Engineering Science 60 (14): 4055-4060.
4. Ho, Raimundo, Sarah E. Dilworth, Daryl R. Williams, and Jerry Y. Y. Heng. 2011. "Role Of Surface Chemistry And Energetics In High Shear Wet Granulation". Industrial & Engineering Chemistry Research 50 (16): 9642-9649.
5. Ho, Raimundo, Steven J. Hinder, John F. Watts, Sarah E. Dilworth, Daryl R. Williams, and Jerry Y.Y. Heng. 2010. "Determination Of Surface Heterogeneity Of D-Mannitol By Sessile Drop Contact Angle And Finite Concentration Inverse Gas Chromatography". International Journal Of Pharmaceutics 387 (1-2): 79-86.
6. Heng JYY, Bismarck A, Lee AF, Wilson K, Williams DR. Anisotropic surface energetics and wettability of macroscopic form I paracetamol crystals. Langmuir. 2006;22:2760-2769.
7. Grzesiak AL, Lang M, Kibum K, Matzger AJ. Comparison of the four anhydrous polymorphs of carbamazepine and the crystal structure of form I. Journal of Pharmaceutical Sciences. 2003;92(11):2260-2271.
8. Smith RR, Williams DR, Burnett DJ, Heng JYY. A new method to determine dispersive surface energy site distributions by inverse gas chromatography. Lagmuir. 2014;30(27):8029-8035.