Cocrystals Mitigate Negative Effects of High pH on Solubility and Dissolution of a Basic Drug

Abstract

Weakly basic drugs are predisposed to order of magnitude decreases in solubility and dissolution as pH increases from 1 to 7 along the gastrointestinal tract. Such behavior is known to be detrimental to drug absorption. The work presented here shows how cocrystals of basic drugs with acidic coformers can mitigate these negative effects. Cocrystals of ketoconazole (KTZ) with adipic, fumaric, and succinic acids exhibit a parabolic solubility dependence on pH such that with increasing pH, solubility decreases, reaches a minimum, and increases. Cocrystals exhibit pHmax values between 3.6 and 3.8, above which they generate supersaturation with respect to drug. Cocrystal supersaturation index (SA), defined as Scocrystal/Sdrug, changes from 1 (pHmax) to 10–30 (pH 5) to 800 – 3,000 (pH 6.5). SA represents the driving force for cocrystal conversion to the less soluble drug during dissolution. SA is not expected to be equal to the observed supersaturation, but it is of great value to classify cocrystals in terms of their risk of conversion. Cocrystal dissolution behavior was analyzed in terms of Cmax, σmax (maximum KTZ concentration and supersaturation), AUCdiss (KTZ concentration area under the curve during dissolution-precipitation), and SA. The three cocrystals studied achieved σmax values between 5 and 15 and sustained supersaturation for 1 to 3 h, resulting in AUCdiss advantage over drug in the range of 2 to 12. SA values as high as 800 were associated with enhanced drug exposure. SA of 3,000 led to limited exposure, very rapid conversion, and no measurable supersaturation. Since cocrystals may be more soluble than needed and/or too soluble to be developed, there is great value in recognizing the relationship between supersaturation threshold, cocrystal solubility, and SA. This becomes more important as cocrystal SA is dependent on pH and other environmental conditions.

Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

“…The cocrystal solubilization can be quantified by the AUC (area under the curve), thus constituting a parameter indicative of the influence that cocrystals have on the API performance. The AUC is directly and inversely proportional to the dissolution and precipitation rates, respectively [49]. Figure 7 shows that unformulated NTZ-SUC cocrystals and NTZ-SUC formulated with 1.0% w/w Methocel ® 60 HG do not lead to improved dissolution profiles when compared to NTZ and the Figure 6a illustrates the dissolution profiles measured over a time interval of 3 h of the unformulated (0.0% w/w of Methocel ® 60 HG) solid phases of pure NTZ, the physical mixture with SUC and the NTZ-SUC cocrystal.…”

Investigation of possible solubility and dissolution advantages of cocrystals, I: Aqueous solubility and dissolution rates of ketoconazole and its cocrystals as functions of pH

“…There are, however, several reports where differences between kinetic solubility of cocrystals and free forms of drug were observed when dissolution rates of powders were studied. It was observed that there were initial increases in drug concentrations, which decreased with time as the free base forms precipitated out [ 17 , 22 , 23 ]. This is analogous to the supersaturation of amorphous drugs prior to their conversion to crystalline forms [ 24 ]; when the solubility reaches equilibrium, any difference between solubility of cocrystal and free drug form diminishes or disappears.…”

“…In contrast to the above-mentioned experimental findings, several investigators have demonstrated through a combination of experimental studies and theoretical calculations that cocrystals can indeed have major solubility advantages over their respective free forms, sometimes by several orders in magnitude [ 22 , 23 , 25 , 26 ]. The higher solubility of cocrystals as the function of pH in these studies were obtained by applying a new 3-step process: first, drug and coformer concentrations in equilibria with cocrystals were measured at pH values of interest; second, cocrystal solubility and solubility product ( K sp ) were determined from the measured equilibrium concentrations; and, third, the pH dependence of cocrystal solubility is theoretically calculated from K sp of cocrystal, p K a values of drug and coformer, and corresponding solubility equations [ 22 ]. Based on such theoretical calculations, Chen et al [ 22 ] observed much higher solubility for 1:1 cocrystals of ketoconazole, a basic drug (p K a 2.94 and 6.51) [ 27 ], with fumaric acid, succinic acid and adipic acid in the pH range of 4 to 7 as compared to that of the free base in the same pH range.…”

“…The higher solubility of cocrystals as the function of pH in these studies were obtained by applying a new 3-step process: first, drug and coformer concentrations in equilibria with cocrystals were measured at pH values of interest; second, cocrystal solubility and solubility product ( K sp ) were determined from the measured equilibrium concentrations; and, third, the pH dependence of cocrystal solubility is theoretically calculated from K sp of cocrystal, p K a values of drug and coformer, and corresponding solubility equations [ 22 ]. Based on such theoretical calculations, Chen et al [ 22 ] observed much higher solubility for 1:1 cocrystals of ketoconazole, a basic drug (p K a 2.94 and 6.51) [ 27 ], with fumaric acid, succinic acid and adipic acid in the pH range of 4 to 7 as compared to that of the free base in the same pH range. Martin et al [ 28 ] also observed 75 to 100 times higher solubility of ketoconazole cocrystals with fumaric acid, succinic acid and adipic acid in water than that of ketoconazole free base.…”

Synthesis and structural characterization of cocrystals of isoniazid and cinnamic acid derivatives

“…Cocrystallization of basic drugs, such as INH, with acidic coformers can mitigate these effects. [17] Moreover, the degradation of RIF and INH due to hydrazone formation in FDC may potentially be countered by masking the hydrazide group through cocrystallization, as well as allowing INH to be combined with an antioxidant in a single tablet. In this present study, hydroxyl derivatives of cinnamic acid were employed to synthesize new cocrystal forms of INH (Scheme 1).…”