Article pubs.acs.org/molecularpharmaceutics
pH-Dependent Solubility of Indomethacin−Saccharin and Carbamazepine−Saccharin Cocrystals in Aqueous Media Amjad Alhalaweh,† Lilly Roy,‡ Naír Rodríguez-Hornedo,*,‡ and Sitaram P. Velaga*,† †
Department of Health Sciences, Luleå University of Technology, Luleå, S-971 87, Sweden Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan, United States 48109-1065
‡
S Supporting Information *
ABSTRACT: Cocrystals constitute an important class of pharmaceutical solids for their remarkable ability to modulate solubility and pH dependence of water insoluble drugs. Here we show how cocrystals of indomethacin−saccharin (IND−SAC) and carbamazepine−saccharin (CBZ−SAC) enhance solubility and impart a pH-sensitivity different from that of the drugs. IND− SAC exhibited solubilities 13 to 65 times higher than IND at pH values of 1 to 3, whereas CBZ−SAC exhibited a 2 to 10 times higher solubility than CBZ dihydrate. Cocrystal solubility dependence on pH predicted from mathematical models using cocrystal Ksp, and cocrystal component Ka values, was in excellent agreement with experimental measurements. The cocrystal solubility increase relative to drug was predicted to reach a limiting value for a cocrystal with two acidic components. This limiting value is determined by the ionization constants of cocrystal components. Eutectic constants are shown to be meaningful indicators of cocrystal solubility and its pH dependence. The two contributions to solubility, cocrystal lattice and solvation, were evaluated by thermal and solubility determinations. The results show that solvation is the main barrier for the aqueous solubility of these drugs and their cocrystals, which are orders of magnitude higher than their lattice barriers. Cocrystal increase in solubility is thus a result of decreasing the solvation barrier compared to that of the drug. This work demonstrates the favorable properties of cocrystals and strategies that facilitate their meaningful characterization. KEYWORDS: cocrystal, solubility, indomethacin, carbamazepine, saccharin, pH, solubility, eutectic point
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INTRODUCTION The Biopharmaceutical Classification System (BCS) for drug molecules is based on their aqueous solubility and intestinal permeation. Drug molecules that permeate the gut wall and exhibit poor solubility are categorized as class II.1 More than 30% of marketed drugs fall into class II under the BCS.2 Despite superior pharmacological properties, these drug molecules risk withdrawal from drug development because of their poor aqueous solubility. Common strategies to improve the solubility of BCS class II compounds include the use of surfactants or complexing agents and amorphous forms, salts or other solid forms of the drug.3−6 There is increasing interest in cocrystal solid forms as a potential solid form to improve the solubility of both ionizable and nonionizable compounds, while retaining their pharmacological activity.7−9 However, there are few in-depth studies on the aqueous solubility of cocrystals.10,11 Mathematical models that describe cocrystal solubility−pH dependence based on solubility product and component ionization have been recently published for 1:1 and 2:1 cocrystals.12 The authors suggested that the use of different coformers in the preparation of cocrystals could be used to engineer the solubility−pH profile of a drug. More remarkably, they showed that it is possible to impart solubility−pH © 2012 American Chemical Society
dependence to nonionizable drugs using an ionizable coformer.12 Cocrystals of indomethacin (IND) and of carbamazepine (CBZ) with many different coformers have been discovered: approximately 8 IND cocrystals and 40 CBZ cocrystals.13−16 Saccharin (SAC), (pKa 1.3−2.2)10,24 forms cocrystals with both IND and CBZ;17−19 IND−SAC and CBZ−SAC were selected to study and compare the aqueous solubility behavior of cocrystals composed of an acidic drug (IND, pKa 4.2)20 with an acidic coformer and a nonionizable drug (CBZ) with an acidic coformer. The bioavailability of IND−SAC and CBZ−SAC cocrystals in simple formulations has been compared with that of marketed products.21,22 Both cocrystals performed as well as the marketed product. Further, the bioavailability of IND−SAC cocrystals was significantly greater than that of a physical mixture of the drug and the coformer. The improved bioavailability of both cocrystals has been explained by the Received: Revised: Accepted: Published: 2605
April 7, 2012 July 27, 2012 August 6, 2012 August 6, 2012 dx.doi.org/10.1021/mp300189b | Mol. Pharmaceutics 2012, 9, 2605−2612
Molecular Pharmaceutics
Article
was conducted at room temperature with a flow rate of 1 mL/ min. UV detection at 319 nm was used for IND, with a mobile phase of 0.2% w/v phosphoric acid and methanol (MeOH), in proportions of 25:75. SAC was detected at 254 nm with a mobile phase of 20% v/v acetic acid adjusted to pH 3 by adding a saturated solution of sodium acetate. The concentrations of CBZ and SAC in the CBZ−SAC cocrystal solution were analyzed using a Waters HPLC 312 (Milford, MA) equipped with a UV/vis spectrometer detector. CBZ and SAC were separated over a C18 Atlantis column (5 μm, 4.6 × 250 mm; Waters, Milford, MA) at ambient temperature. The mobile phase was 55% methanol and 45% water with 0.1% trifluoroacetic acid, and the flow rate was 1 mL/min using an isocratic method. Absorbance of CBZ and SAC was monitored at 284 and 260 nm, respectively. The injection sample volumes were 20 or 40 μL. Differential Scanning Calorimetry (DSC). Thermal analysis of the samples was performed on a DSC Q1000 (TA Instruments) which was calibrated for temperature and enthalpy using indium. Samples (1−3 mg) were crimped in nonhermetic aluminum pans and scanned at a heating rate of 10 °C/min under a continuously purged dry nitrogen atmosphere (flow rate 50 mL/min). The instrument was equipped with a refrigerated cooling system. Powder X-ray Diffraction (PXRD). The PXRD patterns for IND−SAC were recorded on a Siemens D5000 powder diffractometer with Cu Kα radiation (1.54056 Å) that had been previously calibrated using a silicon standard. The tube voltage and amperage were 40 kV and 40 mA, respectively. The divergence slit and antiscattering slit settings were variable for the illumination of the 20 mm sample size. Samples were scanned over a range of 2θ between 5 and 40° with a step size of 0.02° and a time per step of 1 s. The PXRD patterns for the CBZ−SAC system studies were collected by a benchtop Rigaku Miniflex X-ray diffractometer (Danvers, MA) using Cu Kα radiation (λ = 1.54 Å), a tube voltage of 30 kV, and a tube current of 15 mA. Data were collected from 2 to 40° at a continuous scan rate of 2.5° min−1.
increased solubility of the cocrystal components. However, there is a need for understanding cocrystal solubility in aqueous media and its dependence on the pH and ionization of the components. The aim of this study was to investigate the solubility−pH dependence of IND−SAC and CBZ−SAC cocrystals. The specific objectives were (1) to evaluate the solubility product (Ksp) for both cocrystals and to predict the solubility−pH dependence of the cocrystals using appropriate models, (2) to provide insights on the solubility advantage offered by cocrystals and the relative contribution of lattice energy and solvation to the solubility, and (3) to measure the cocrystal solubility, and eutectic constant dependence on pH.
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EXPERIMENTAL SECTION Materials. SAC and the gamma form of IND were purchased from Sigma-Aldrich (Stockholm, Sweden). Anhydrous monoclinic CBZ (III) and SAC were purchased from Sigma-Aldrich (St. Louis, MO). Milli-Q water was used, and all chemicals and solvents were used as received. CBZ dihydrate (CBZD) was prepared from aqueous slurry conversion of CBZ (III). Preparation of Cocrystals. IND−SAC cocrystals were prepared using the solvent evaporation method. A mixture of IND (0.01 M, 3.578 g) and SAC (0.01 M, 1.832 g) was dissolved in 200 mL of ethyl acetate and heated to aid dissolution. The solution was left at room temperature (∼22 °C) in a controlled fume hood (air flow 0.54 m/s). The resulting crystals were filtered and dried in a desiccator over silica gel to ensure complete dryness.23 CBZ−SAC cocrystals were prepared using the reaction crystallization method in ethanol at room temperature, by adding carbamazepine to nearly saturated solutions of SAC. The phase purity of all powders obtained was verified by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Solubility of Cocrystal Components. The solubility of IND and CBZD was measured in a pH range of 1−7 and 1−3 respectively (adjusted by addition of 1 M HCl or 1 M NaOH) at 25 °C. An excess amount of each material was slurried in a solution for 72−96 h. After equilibration, the solutions were filtered, diluted and analyzed by high-performance liquid chromatography (HPLC). The solid forms in equilibrium were the stable polymorphs of IND (γ-form) and CBZD confirmed using PXRD. Measurement of Cocrystal Solubility. The eutectic point between cocrystal and drug was reached by suspending 50−100 mg of cocrystal and 25−50 mg of drug in 3 mL of aqueous solution with continuous stirring (360 rpm) until equilibrium was reached (72−96 h) at 25 ± 0.1 °C. A detailed discussion of eutectic point measurements has been discussed elsewhere.24 Solution pH was varied by the addition of small volumes of 1 M HCl or 1 M NaOH, and the pH at equilibrium was measured. Equilibrium solution concentrations of drug and coformer at eutectic point between solid cocrystal and drug were analyzed by HPLC. Solid phases at equilibrium were confirmed by PXRD. High-Performance Liquid Chromatography (HPLC) Methods. Solutions of the IND−SAC cocrystals were analyzed by HPLC (series 200 binary LC pump and 200 UV−vis detector, TotalChrom software, Perkin-Elmer, Wellesley, MA). IND and SAC were separated over a C18 column (Dalco Chrometch, 5 μm, 150 mm × 4.6 mm). The HPLC analysis
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RESULTS AND DISCUSSION The solubility of a cocrystal with one or two acidic monoprotic components has been previously derived, by considering the cocrystal dissociation and the ionization of its components.12 IND−SAC cocrystal has two ionizable, acidic components, with pKa values of 4.2 and 1.6 for IND and SAC respectively. The solubility dependence on [H+] is given by SIND − SAC =
⎛ K IND ⎞⎛ K SAC ⎞ K sp⎜1 + a + ⎟⎜1 + a + ⎟ [H ] ⎠⎝ [H ] ⎠ ⎝
(1)
where Ksp is the cocrystal solubility product, and KIND and KSAC a a are the ionization constants of cocrystal components. For the CBZ−SAC cocrystal with only one ionizable, acidic component its solubility is given by SCBZ − SAC =
⎛ K SAC ⎞ K sp⎜1 + a + ⎟ [H ] ⎠ ⎝
(2)
The above equations describe equilibrium solubility behavior. These cocrystals converted to drug solid phases when suspended in water or buffer and required solubility measurement at the eutectic point, where the solution phase is in equilibrium with both cocrystal and drug solid phases.12 2606
dx.doi.org/10.1021/mp300189b | Mol. Pharmaceutics 2012, 9, 2605−2612
Molecular Pharmaceutics
Article
Cocrystal Ksp. The Kspwas calculated from the total solution concentrations of coformer ([coformer]eu) and drug ([drug]eu) in equilibrium at the eutectic point using equations of the general form [coformer]eu =
K sp [drug]eu
eutectic according to the following equation for a 1:1 cocrystal (regardless of ionization): Scocrystal =
(3)
⎛ K IND ⎞⎛ K SAC ⎞ ⎜ 1 + a + ⎟⎜ 1 + a + ⎟ [IND]eu ⎝ [H ] ⎠⎝ [H ] ⎠ K sp
(4)
Measurements were conducted in a pH range between 1 and 3. Equilibrium pH values could not be independently adjusted above a pH of 3, as [SAC] overwhelmed the buffer capacity of the solution. For a cocrystal of a nonionizable drug and an acidic coformer, CBZ−SAC, [coformer]eu dependence on [H+] is [SAC]eu =
⎛ K SAC ⎞ ⎜1 + a + ⎟ [CBZ] eu ⎝ [H ] ⎠ K sp
(5)
Scocrystal
Ksp for IND−SAC and CBZ−SAC cocrystals were determined using nonlinear regression analysis of the experimental data according to eqs 4 and 5. The experimental results were well described by the nonlinear regression analysis, for IND−SAC (r2 = 0.91, P < 0.002 for [SAC]eu) and CBZ−SAC (r2 = 0.91,
