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The Mechanism of Phenytoin Crystal Growth

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The Mechanism of Phenytoin Crystal Growth International Journal of Pharmaceutics, 98 (1993) 189-201 189 0 1993 Elsevier Science Publishers B.V. All rights reserved 0378-5173/93/$06.00 IJP 03264 The mechanism of phenytoin crystal growth Gail L. Zipp ’ and Nair Rodriguez-Horned0 College of Pharmacy, The Universi@ of Michigan, Ann Arbor, MI 48109-1065 (USA) (Received 6 August 1992) (Modified version received 8 March 1993) (Accepted 18 March 1993) Key words: Phenytoin; Crystal growth; Kinetics; Mechanism Summary Phenytoin crystal growth kinetics have been measured as a function of pH, supersaturation and temperature in phosphate buffer. Incorporation of growth units into the crystal lattice was not influenced by diffusion from the bulk to the solid surface. Thus, the rate limiting step for phenytoin growth is surface integration. Phenytoin crystal growth is via a screw-dislocation mechanism; this mechanism explains the observed dependence of growth rate on supersaturation and the increase in growth rate with pH. Introduction bility of these compounds is dependent on pH, in vitro and in vivo crystallization of the free acid or An understanding of crystallization mecha- base can occur as a result of a pH change. In nisms is necessary for the prediction of solids vivo, precipitation follows either dissolution of a properties which influence the dissolution rate solid phase or dilution of a solution of the salt of and bioavailability of oral dosage forms such as a weak acid or base. Precipitation via a pH change particle size, size distribution and morphology. In is also commonly used in industrial crystalliza- addition, formulation of non-precipitating dosage tion. forms requires an understanding of the condi- Previous investigations have highlighted this tions under which crystals will form so that limit- phenomenon. Serajuddin (1990) studied the dis- ing conditions for non-precipitating systems can solution of the sodium salt of phenytoin (NaDPH) be evaluated. and observed crystallization of the acid (DPH) in Many systems of pharmaceutical importance the pH range of l-8. Higuchi et al. (1965) ob- contain weak acids or weak bases. Since the solu- served a similar behavior during the dissolution of sodium tolazamide. Newton and Kluza (1980) and Salem et al. (1980) have reported crystalliza- tion of DPH as a result of dilution of a solution Correspondence to: N. Rodriguez-Hornedo, College of Phar- of NaDPH. Even though the more soluble salts macy, The University of Michigan, Ann Arbor, MI 48109-1065, U.S.A. are often the choice in a formulation, crystalliza- ’ Present address: The Upjohn Company, 301 Henrietta St, tion of the unionized species may be a controlling Kalamazoo, MI 49007, U.S.A. factor in drug delivery. 190 The purpose of the work presented here was strength of 0.16 and reported the apparent disso- to study the mechanism and kinetics of DPH ciation constant, pK,, to be 8.06 and the solubil- crystal growth as a function of supersaturation, ity of the unionized form to be 18.4 pg/ml. The pH and temperature. solubility of phenytoin can be calculated as a function of pH from Eqn 4 and is shown in Fig. 1. Background Theoretical aspects of crystal growth from solution Phenytoin (Mol. Wt 252.3) is a weak acid whose The growth of crystals from solution involves a structure is shown in Fig. 1. The sodium salt is series of steps by which a growth unit passes from highly dissociated in water and the anion can the bulk solution to the crystal lattice. They in- react to form the undissociated acid according to clude: transport of growth units from the bulk the following equilibria: solution to the crystal surface, adsorption of growth units onto the solid surface, possible dif- Na+(DPH)- s Na++ (DPH)- (1) fusion of the growth units from the point of adsorption to a favorable incorporation site and (DPH) - + H,O+ = DPH+H,O (2) integration into the crystal lattice. The rate of growth is limited by the slowest of these pro- The total phenytoin solubility, S, can be ex- cesses. pressed as a function of the hydrogen ion concen- There are several possible sites for incorpora- tration, [H+], the solubility of the unionized form, tion into the crystal lattice. Interaction between a S,, and the dissociation constant for DPH, K,: growth unit and the crystal lattice is greatest at a kink site, where bonds are formed in three direc- S = S, + (DPH) - = S, + K,S,/[H+] tions. Bonds are formed in two directions at step sites and in only one direction at ledge sites. This can be transformed into the more com- Thus, incorporation into the lattice occurs pre- mon pH and pK, notation as: dominately at kink sites. The growth unit can be an ion, a single log( S/S, - 1) = pH - pK, (4) molecule or two or more molecules interacting in solution. During the growth process, solvent Schwartz et al. (1973) measured the solubility growth-unit interactions in solution are replaced of the free acid in phosphate buffer at an ionic by solid-solid bonds in the crystal lattice. Adsorp- tion onto the crystal surface results in a partial 10’ desolvation of the growth unit. Incorporation into a kink site then completely replaces the kink- H I solvent interaction with solid-solid interaction. The driving force for crystallization, the super- saturation, is the difference in chemical potential of the substance, i, in solution, pi, and in a solution at equilibrium with the solid phase, pi,eq (i.e., a saturated solution): Api = pi - CLi,eq (5) PH Writing the chemical potential as: Fig. 1. Phenytoin solubility as a function of pH at 25°C (after Schwartz et al., 1977): measured solubility, (- ) cal- (0) yi=poi+RT In ai=poi+RT In culated solubility. Yici (6) 191 where P“~ is the chemical potential of i in the rounding the crystal and the diffusion rate of the standard state, and the activity of i in solution, growth units. a,, is the product of the activity coefficient, -yi, and the concentration of i, Ci, Eqn 5 becomes: Surface integration control APi/RT = 14aJai,eq > = ln(YiCi/Yi,eqCi,eq) (7) A large body of theoretical work has been devoted toward the development of models that If the activity coefficient is not a strong func- describe the formation and propagation of kink tion of concentration, the ratio y/~~,,~ is close to sites on the crystal surface. If the surface is very unity and the supersaturation, (+, becomes rough and covered with kinks, every encounter of a growth unit with the solid is likely to be at a site u = Ap/RT z In{ Ci/Ci,eq) (8) favorable for incorporation. This type of growth usually occurs at high temperatures and is said to be due to a rough surface mechanism. Growth rate becomes a linear function of the driving Crystal growth mechanisms force, u (Weeks and Gilmer, 19791, as: The rate-limiting step for crystal growth is G =A,a (10) frequently assigned to two general categories: dif- fusion control, and surface integration control. If Crystal growth occurring by this mechanism tends diffusion of growth units from the bulk solution to result in rounded, non-facetted crystals. to the crystal surface is slow compared to integra- At lower temperatures, crystal growth occurs tion into the lattice, growth is diffusion con- by a layer mechanism; growth units are integrated trolled. Otherwise, if diffusion is fast compared to at kink sites on a flat crystal surface. Two mecha- integration, the solute concentration at the crys- nisms have been proposed as the source of kink tal surface is equal to the bulk concentration and sites, as described below. growth is controlled by surface integration. Both of these categories are discussed in further detail Two-dimensional nucleation where nuclei form on below. the crystal and spread across the flat sugace The mechanism of crystal growth can be deter- This process is somewhat analogous to ho- mined by analyzing the predicted growth rate mogenous nucleation. Clusters of growth units dependence on crystallization conditions and continually form and dissolve on the crystal sur- comparison of the predictions with measured ki- face. When the radius of a cluster exceeds a netic data. critical value, r *, the excess free energy of the cluster is at a maximum, AG*, and the nucleus Diffusion control can grow. As with homogeneous nucleation, the rate of clusters attaining the critical size is strongly In the case of diffusion control, crystal growth dependent upon supersaturation, being essen- is limited by the rate of transport of growth units tially zero at low supersaturation and rapidly across a boundary layer to the crystal surface. increasing to a constant value at higher supersat- The crystallization rate would follow Fick’s law of uration. diffusion (Ohara and Reid, 1973) and the growth There are two main models describing two-di- rate, G, is proportional to the driving force: mensional nucleation: mononuclear models, where only one nuclei can form on a given crystal G =A,a (9) face, and birth and spread or polynuclear models, where more than one nuclei can form on a face In this case the rate constant, A,, depends upon and where nuclei can form on top of other grow- the diffusion boundary layer thickness, S, sur- ing nuclei. 192 Numerous equations have been derived to de- Eqn 13 can be simplified in the moderately low scribe the dependence of growth rate on super- supersaturation region where the term C,/ saturation for the two-dimensional nucleation (Ap/RT) is small (Ohara and Reid, 1972) as: mechanism. The one used here was developed by Gilmer and Bennema (1972) for the birth and G = C, *Ap/RT * ( eAFIRT- 1) ( 14a) spread model and is: The value of the constant C, in Eqn 14a is G = B,( Ap/RT)5/6.
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