Effect of diffusion layer pH and solubility on the dissolution rate of pharmaceutical bases and their hydrochloride salts. I: Phenazopyridine

The pH-solubility profile of phenazopyridine as determined by the addition of HCl or NaOH solutions to its aqueous suspension was identical to that of its hydrochloride salt except during phase transition from base to salt. With the addition of HCl to a suspension of the base, the pH dropped to a certain point and then remained constant until a supersaturated solution was formed. Only after a high supersaturation did precipitation of the hydrochloride salt occur. The solubility of the salt decreased at low pH due to a common ion effect. Unlike solubility profiles, the pH-intrinsic dissolution rate profiles of the base and its salt differed greatly. At low pH, the dissolution rate of the hydrochloride salt decreased with an increase in HCl concentration, whereas the dissolution rate of the base increased. The self-buffering action of the base and the increase in solubility, leading to a supersaturation of the diffusion layer was responsible for the increase in its dissolution rate with a lowering of the pH of the medium. Good conformity with the Noyes-Whitney equation was demonstrated when the solubility values under pH conditions such that the diffusion layer thickness approaches zero (Cs,h = 0) were used rather than solubilities under pH conditions of the bulk media (Cs). Supersaturation of the dissolution medium was observed during dissolution of the hydrochloride salt at pH 7.     

Effect of chloride ion on dissolution of different salt forms of haloperidol, a model basic drug

The effect of chloride ion (Cl-) on dissolution rates of hydrochloride, mesylate (methanesulfonate) and phosphate salt forms of a model drug, haloperidol, was investigated. The dissolution rates of the salts in 0.01 M HCl from rotating disks followed the order of mesylate>phosphate>hydrochloride. With additional chloride ion, a decrease in dissolution rate of the hydrochloride salt was observed due to the common ion effect. Dissolution rates of mesylate and phosphate salts also decreased due to their conversion to the HCl salt form on the surfaces of dissolving disks, however, the dissolution rates of mesylate and phosphate salts under identical chloride ion concentrations were still higher than that of the HCl salt. In powder dissolution studies, it was observed that kinetics of nonhydrochloride-to-hydrochloride salt conversion play a major role in dissolution; the mesylate dissolved completely (<5 min) before its dissolution rate could be impeded by its conversion to the hydrochloride salt form. Therefore, despite the potential for conversion to a hydrochloride salt form, certain nonhydrochloride salt forms may still be preferred for dosage form development due to kinetic advantages during dissolution, such as higher apparent dissolution rate of a nonhydrochloride salt before it could completely convert to the hydrochloride form.     

Unusual solubility and dissolution behavior of pharmaceutical hydrochloride salts in chloride-containing media

The pH-solubility profiles of 3 pharmaceutical hydrochloride salts were determined in sodium acetate-hydrochloric acid buffer. Unusual pH-solubility profiles containing maxima at pH 4–6 were observed for phenazopyridine hydrochloride, cyproheptadine hydrochloride and bromhexine hydrochloride. The decrease in solubility at lower pH values was attributed to the common ion effect of chloride on the solubility product equilibrium of the hydrochloride salts. The dissolution behavior of the free bases and that of the hydrochloride salts of these drugs were compared in dilute hydrochloric acid solution, in pH range from 1.0 to 3.0. The apparent dissolution rates and solubilities of these hydrochlorides were less than those of the respective free base forms in the pH range of the stomach (pH 1.0–2.0). These results substantiated further the contention that the salt formation does not always result in an enhancement of solubility characteristics.     

Importance of using physiologically relevant volume of dissolution medium to correlate the oral exposure of formulations of BMS-480188 mesylate

BMS-480188 is a weak base. The aqueous solubility of BMS-480188 is 0.036 mg/ml at pH 6.5 at 37 degrees C. The mesylate salt of BMS-480188 was prepared to improve its solubility. Capsules containing mesylate salt alone (Formulation A) or mesylate salt with excipients, including lactose, croscarmellose sodium, sodium lauryl sulfate, syloid and magnesium stearate (Formulation B), were prepared. Both formulations show similar dissolution profiles in 1l 0.01N HCl at 37 degrees C. However, the bioavailability of Formulations A and B is 5.7 and 24%, respectively, in monkeys. Since very small amount of fluid is available in the stomach of monkeys in fasted state, 30 ml of 0.01N HCl was used as the dissolution medium to simulate the ratio of the drug to dissolution medium in vivo. The dissolution studies in 30 ml of 0.01N HCl show that the amount of drug dissolved from the Formulation B is 80% greater than the Formulation A after 2h. These results are consistent with the higher bioavailability of the formulated capsules. The pK(a) of the free base is 3.0 and the apparent solubility of the mesylate salt (>20mg/ml) is much greater than the equilibrium solubility of BMS-480188 (1.08 mg/ml) in 0.01N HCl at 37 degrees C. Therefore, the mesylate salt of BMS-480188 converts to the free base in 0.01N HCl. The presence of excipients delays the conversion of the mesylate salt to the free base in the dissolution test using 30 ml medium, leading to a greater percentage of the dissolved drugs. This inhibitory effect of excipients is masked during the dissolution using 1l medium because the concentration of the dissolved drug is below the solubility limit of BMS-480188. This study demonstrates the importance of the volume of the dissolution medium for the in vitro dissolution test to qualitatively predict the bioavailability of a salt of weak base with low intrinsic aqueous solubility.     

Role of Salt and Excipient Properties on Disproportionation in the Solid-State

Purpose  Approximately 50% of active pharmaceutical ingredients (APIs) are manufactured and formulated as salts, due to their enhanced dissolution rates or improved solid state properties. It is essential to maintain the appropriate solid state form of the drug during processing and over the lifetime of the product. The aim of this study was to investigate the contributing factors in the process of disproportionation, whereby the salt converts back to the free form of the drug. Methods  Infrared and Raman spectroscopy were used to detect and quantify the formation of free base in physical mixtures with excipients. The pH-solubility relationships were determined based on measured salt solubilities and properties of the free form. Results  The mesylate salts of two model pharmaceutical compounds were found to disproportionate to the free base form when physically mixed with certain common basic excipients and exposed to moderate relative humidities. In contrast, the napsylate salts were much more resistant to disproportionation. The napsylate salts had solubilities more than 3 orders of magnitude lower than the respective mesylate salts, and showed little to no detectable formation of free base. The mesylate salts with higher solubilities showed significant levels of conversion to the free base. Conclusions  It appears that both the solubility and pH_max (the pH of a solution where there is saturation of both ionized and unionized species) of the salts, as well as the base solubility, play important roles in determining the susceptibility of salts to disproportionate. The extent of conversion was also affected by excipient properties, including basicity, solubility, physical state and surface area.     

Solution-mediated phase transformation of salts during dissolution: investigation using haloperidol as a model drug

Soluble salts can undergo solution-mediated phase transformation to a lower solubility form due to pH gradients in the gastrointestinal tract. Therefore, dissolution rate rather than solubility may be the best predictor of bioavailability for such compounds. The purpose of this project was to examine the kinetics of the conversion of a basic compound, haloperidol, and its salt forms using a flow-through dissolution apparatus and rotating disk method in neutral conditions. The effects of buffer concentration, salt form, dissolution apparatus, and hydrodynamics were examined. Raman microscopy was used to characterize solids after dissolution. Haloperidol mesylate and haloperidol chloride showed a decrease in dissolution rate with time in the dissolution media. Haloperidol mesylate and haloperidol chloride dissolution rates also decreased with increasing buffer capacity. Raman microscopy confirmed phase conversion from the salt forms to the free base form in phosphate buffer. Hydrodynamics did not affect the time course of the solution-mediated phase transformation of salt forms. Dissolution and precipitation appear to be a function of pH close to the surface of the dissolving solid. In situations where equilibrium solubility of salts cannot be assessed experimentally, dissolution experiments are useful for examining the extent and duration of the dissolution rate enhancement.     

pH-Solubility Profiles of Organic Bases and Their Hydrochloride Salts

Knowledge of comparative solubility profiles of a base and its hydrochloride salt is important in selecting one form over the other for dosage form design. The studies with two model bases, namely, tiaramide and papaverine, showed that, except during phase transition from a base to a salt or vice versa, the pH-solubility profiles are identical whether a base or a salt are used. The solubilities were determined by equilibration after addition of hydrochloric acid or sodium hydroxide solutions to suspensions of bases and salts. With the addition of hydrochloric acid solution, the pH values of the suspensions of tiaramide and papaverine dropped to 5.0 ± 0.1 and 4.0 ± 0.1, respectively, and then remained constant until supersaturated solutions were formed. After nucleation of supersaturated solutions with the addition of hydrochloride salt or the reduction of temperature, the precipitation of hydrochloride salt occurred. The solubilities of salts decreased at low pH due to common ion effect. The K^o _sp values, however, did not remain constant and the solubility profiles showed positive deviations from the theoretical ones. These may be due to a possible self-association and the resultant difference between the solubilities and activities of the compounds in solutions. The reported differences between the solubilities of bases and their respective hydrochloride salts at a particular pH and the lack of common ion effects on the solubilities and dissolution rates of bases are explained.     

Preformulation study of a poorly water-soluble drug, alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol: selection of the base for dosage form design

The physicochemical properties of the base and hydrochloride salt of the poorly water-soluble drug alpha-pentyl-3-(2-quinolinylmethoxy) benzenemethanol (REV 5901) were investigated in order to select an appropriate form of the drug for dosage form development. The pH-solubility profiles of both the base and the salt at 37 degrees C were identical and were in agreement with a pKa value of 3.67 determined by the UV spectral method. The solubility of the drug (approximately 0.002 mg/mL at pH 6) increased gradually with a decrease in pH and reached a value of 0.95 mg/mL at pH 1; at pH values less than 1, the solubility decreased due to the common-ion effect. The pHmax, i.e., the pH of maximum solubility of the drug was, therefore, 1.0. The role of the pHmax in the selection of a salt or base form of a compound was investigated. Due to the conversion of the salt to the base at the surface of the dissolving solid at pH values greater than pHmax, the dissolution rates of both the base and the salt were identical. In the solid state, the salt existed in anhydrous and monohydrate forms; the anhydrous salt converted to the hydrate at greater than 40% relative humidity, and the hydrate lost water at 40-60 degrees C. The thermal properties of the salt were indicative of its potential instability, which was confirmed by accelerated stability studies. The base existed in a stable crystalline solid form, and also in an oily liquid form which converted to crystals on standing.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dissolution rates of doxycycline free base and hydrochloride salts.

The dissolution rates of doxycycline monohydrate, hyclate, and hydrochloride dihydrate crystal forms were investigated using the static pellet method. Solubility product equilibria with chloride ion strongly suppressed the dissolution rate of the hydrochloride dihydrate salt. This form dissolved about fourfold slower in 0.1 N HCl than in water, which was consistent with its solubility in these media. Specificity for chloride was demonstrated by the rapid dissolution rate for the hydrochloride dihydrate in 0.1 N methanesulfonic acid. The dissolution rates of the hyclate, a solvated hydrochloride salt, and the free base were not sensitive to chloride ion. The results show that common ion equilibria with chloride can strongly reduce the dissolution rate of a thermodynamically stable hydrochloride salt form, while the free base or a metastable hydrochloride salt are not similarly affected.     

Effect of diffusion layer pH and solubility on the dissolution rate of pharmaceutical acids and their sodium salts. II: Salicylic acid, theophylline, and benzoic acid

The pH-solubility profiles of salicylic acid and theophylline, as determined by the addition of HCl or NaOH to their aqueous suspensions, were identical with those of their sodium salts except during phase transitions from acid to salt or vice versa. Supersaturated solutions were formed during phase transitions. Unlike the solubility profiles, the pH-intrinsic dissolution rate profiles of an acid and its salt differed greatly. Good conformity with the Noyes-Whitney equation was demonstrated when the solubility values under pH conditions as the diffusion layer thickness, h, approaches zero (Cs,h = 0) were used rather than solubilities under pH conditions of the bulk media (Cs). The pH when h approaches zero (pHh = 0) was estimated by equilibration of a dissolution medium with an excess of material. Good correlation was shown between the pHh = 0 values of benzoic acid estimated according to this method and the pHh = 0 values reported in the literature. The intrinsic dissolution rate constant, the ratio of the diffusion coefficient to the diffusion layer thickness (D/h), may be assumed constant when comparing the dissolution rates of salicylic acid, theophylline and sodium theophylline. On the other hand, D/h decreased significantly during dissolution of sodium salicylate due to a large increase in Cs,h = 0 and the consequent increase in viscosity in the diffusion layer. A simple method of predicting the dissolution rate of an acid or a salt at different pH values has been developed.     

Phosphate buffer interferes dissolution of prazosin hydrochloride in compendial dissolution testing

The purpose of this study was to elucidate the lack of supersaturation behavior in the dissolution profile of prazosin hydrochloride (PRZ-HCl) in the compendial dissolution test. The equilibrium solubility was measured by a shake-flask method. Dissolution tests were performed by a compendial paddle method with a phosphate buffer solution (pH 6.8, 50 mM phosphate). The solid form of the residual particles was identified by Raman spectroscopy. In the pH range below 6.5, the equilibrium solubility in phosphate buffer was lower than that in the unbuffered solutions (pH adjusted by HCl and NaOH). Raman spectra showed that the residual solid was a phosphate salt of PRZ. In the pH range above 6.5, the pH-solubility profiles in the phosphate buffer solutions and the unbuffered solutions were the same. The residual solid was a PRZ freebase (PRZ-FB). In the dissolution test, PRZ-HCl particles first changed to a phosphate salt within 5 min, then gradually changed to PRZ-FB after several hours. Since the intestinal fluid is buffered by the bicarbonate system in vivo, the dissolution behavior in vivo may not be properly evaluated using a phosphate buffer solution. For drugs with a low phosphate solubility product, it is necessary to consider this aspect.     

Salt formation to improve drug solubility

Salt formation is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs. In this article, physicochemical principles of salt solubility are presented, with special reference to the influence of pH-solubility profiles of acidic and basic drugs on salt formation and dissolution. Non-ideality of salt solubility due to self-association in solution is also discussed. Whether certain acidic or basic drugs would form salts and, if salts are formed, how easily they would dissociate back into their free acid or base forms depend on interrelationships of several factors, such as S0 (intrinsic solubility), pH, pKa, Ksp (solubility product) and pHmax (pH of maximum solubility). The interrelationships of these factors are elaborated and their influence on salt screening and the selection of optimal salt forms for development are discussed. Factors influencing salt dissolution under various pH conditions, and especially in reactive media and in presence of excess common ions, are discussed, with practical reference to the development of solid dosage forms.     

Solubility of doxycycline in aqueous solution.

The solubility of doxycyline monohydrate and doxycycline hydrochloride dihydrate was investigated in aqueous solution. The hydrochloride dihydrate salt was isolated and identified from solutions initially containing doxycycline hyclate in water. The pKa' = 3.09 (mu = 0.1 and 25 degrees) for protonation of doxycycline was determined spectrophotometrically. The pH-solubility profiles were determined for doxycycline monohydrate in water and in 1.0 M NaNO3-HNO3 and NaCl-HCl. The pH-solubility profile at 25 degrees for doxycycline in aqueous hydrochloric acid without added salt reached a sharp maximum fo 50 mg/ml at pH 2.16. Added chloride ion strongly suppressed the solubility of the hydrochloride dihydrate salt. The apparent solubility product was not constant but decreased as the concentration of added salt increased. A theoretical model was developed involving dimerization of doxycycline and applied to the experimental data. The dimerization constant, Kd = 24 M-1, and true solubility product, K0sp = 1.8 X 10(-3) M2, were calculated. The effect of concentration on NMR and visible spectra indicated that dimerization resulted from intermolecular hydrogen bonding of the phenolic beta-diketone portion of the molecule.     

pH-Solubility profile of papaverine hydrochloride and its relationship to the dissolution rate of sustained-release pellets

The pH-solubility profile of papaverine hydrochloride (I) was determined using the phase-solubility technique and equilibrium solubilities in buffers. The release of I from sustained-release pellets consisting of a shellac-based matrix was determined by the USP basket technique and was found to exhibit zero-order kinetics. Release rates at various pH values of the permeating solvent were compared with the pH-solubility profile and were directly proportional to the solubility below, but not above, the apparent pHmax (3.9). This lack of proportionality was also shown by the intrinsic dissolution rates. The effect was attributed to the self-buffering action of I and the metastability of the papaverine salt-base system in the vicinity of pHmax. It is postulated that the outer layer of polymer and filler on the surface of the pellets forms a barrier which determines the rate of release. The inner matrix serves as a drug reservoir in which the internal pH may not be the same as the bulk pH.     

Influence of the Solid Form of Siramesine Hydrochloride on its Behavior in Aqueous Environments

Purpose  To study the influence of solid form on the behavior of the salt siramesine hydrochloride in aqueous environments. Methods  The solubilities and dissolution rates of siramesine hydrochloride anhydrate and monohydrate were determined at pH 3.4 and 6.4, and precipitates were examined by X-ray powder diffraction. The mechanism of anhydrate–hydrate conversion was investigated by optical microscopy, and wet massing of the anhydrate was carried out using water and 60% (v/v) ethanol separately as granulation liquids. The wet masses were analyzed using Raman microscopy. Results  At pH 3.4 the anhydrate and monohydrate salts exhibited similar dissolution profiles. At pH 6.4 both the anhydrate and monohydrate salts formed supersaturated solutions of high apparent solubility. From the anhydrate solution, precipitation of the free base occurred, while the solution of the monohydrate salt remained in the supersaturated state. This resulted in a superior dissolution profile of the monohydrate salt. Microscopy and wet massing experiments showed that the anhydrate–hydrate conversion of siramesine hydrochloride was solution-mediated and dissolution-controlled. Conclusion  During development of a formulation based on the anhydrate salt, the risk of processing-induced transformation to the monohydrate form as well as precipitation of the free base should be considered.     

General treatment of pH-solubility profiles of weak acids and bases and the effects of different acids on the solubility of a weak base

The pH-solubility profile of a weak acid or base is shown to be a function of its pKsp, pKa, and uncharged species solubility. Equations are presented that can be used to calculate the solubility as a function of pH. These equations can also be used when there is added salt present. Experimental data was obtained in three cosolvent systems consisting of methanol-water and ethanol-water. Also, the effect of different acids on the solubility of a weak base is reported. A pronounced effect on the solubility by the addition of salt is explained in terms of the Ksp.     

Mechanistic Analysis of Cocrystal Dissolution,Surface pH,and Dissolution Advantage as a Guide for Rational Selection

The dissolution behavior of a dibasic drug ketoconazole under the influence of pH has been evaluated and compared to its three 1:1 cocrystals with diacidic coformers, fumaric acid, succinic acid (SUC), and adipic acid. Mass transport models were developed by applying Fick's law of diffusion to dissolution with simultaneous chemical reactions in the hydrodynamic boundary layer adjacent to the dissolving surface to predict the interfacial pH and flux of the parent drug and cocrystals. All 3 cocrystals have the ability to modulate the interfacial pH to different extents compared to the parent drug due to the acidity of the coformers. Dissolution pH dependence of ketoconazole is significantly reduced by the cocrystallization with acidic coformers. Due to the different dissolution pH dependence, there exists a transition pH where the flux of the cocrystal is the same as the parent drug. Below this transition pH, the drug flux is higher, but above it, the cocrystal flux is higher. The development of these mass transport models provide a mechanistic understanding of the dissolution behavior and help identify cocrystalline solids with optimal dissolution characteristics.     

Supersolubilization and Amorphization of a Model Basic Drug, Haloperidol, by Interaction with Weak Acids

Purpose

To present a novel approach of greatly enhancing aqueous solubility of a model weakly basic drug, haloperidol, by using weak acids that would not form salts with the drug and to attain physically stable form of amorphous drug by drying such aqueous solutions.

Method

Aqueous solubility of haloperidol in presence of increasing concentrations of four different weak organic acids (malic, tartaric, citric, fumaric) were determined. Several concentrated aqueous solutions with differing drug-to-acid molar ratios were dried in vacuum oven, and dried materials were characterized by DSC, powder XRD, dissolution testing, and stability study.

Result

Acids were selected such that they would not form salts with haloperidol. Haloperidol solubility increased greatly with increased concentrations of malic, tartaric and citric acids, reaching >300 mg/g of solution. In contrast to the haloperidol HCl aqueous solubility of 4 mg/g, this may be called supersolubilization. Fumaric acid did not cause such solubilization as it had low water solubility. Dried solids formed dispersions of amorphous haloperidol in acids that were either amorphous or partially crystalline. Amorphous haloperidol was physically stable and had better dissolution rate than HCl salt.

Conclusion

A novel method of drug solubilization in aqueous media by acid–base interaction is presented. Physically stable amorphous systems of drugs may also be prepared by using this organic solvent-free approach.     

Mechanistic analysis of pH-dependent solubility and trans-membrane permeability of amphoteric compounds: application to sildenafil

This study was aimed at investigating the pH-dependent solubility and in vitro transmucosal permeability of sildenafil, an amphoteric compound with limited aqueous solubility, across parallel artificial membrane. The aqueous solubility and permeability of sildenafil as a function of solution pH were theoretically derived from the individual contributions of all species (cationic, neutral and anionic). The stability, octanol-water distribution coefficient (log D), and solubility of sildenafil were then determined at various pHs, the permeability study was also performed at different pHs using parallel artificial membrane. The pH-solubility and -permeability profiles were then fitted to theoretical equations using non-linear regression. The experimental pH-solubility profile was fitted very well to the theoretical equations (R(2)=0.9996). The in vitro permeability of saturated sildenafil solution at different pH values also showed similar trend as the predicted one (R(2)=0.7829). The two optimum pH (pH(max)) values were found to be 4.50 and 10.24, where the maximum solubility of either cationic or neutral species, or anionic and neutral species is simultaneously obtained, and the maximal transmucosal fluxes (J(ss)) are achieved. The above method can be applied to optimize the transmucosal delivery of other amphoteric drugs with low aqueous solubility.     

Tablet Dissolution Affected by a Moisture Mediated Solid-State Interaction Between Drug and Disintegrant

Purpose. To investigate the cause for decrease in delavirdine mesylate 200 mg tablet dissolution upon exposure to high humidity. Methods. Dissolution testing was performed using the USP 2 (paddle) apparatus. Water in tablets was measured by Karl Fischer titration. ¹³C CP/MAS NMR was used to identify and quantify delavirdine form changes in tablets. FT-IR spectroscopy was used to monitor delavirdine form change in tablets and component mixes, and to investigate a solid state reaction with the disintegrant. Results. Dissolution extent of delavirdine mesylate 200 mg tablets was substantially decreased after exposure to high humidity. This effect is related to the amount of water present in the tablet matrix. ¹³C CP/ MAS NMR detected about 30% conversion from the mesylate salt of delavirdine to its free base form in the tablet matrix. FT-IR spectroscopy demonstrated that a solid state reaction occurs between the freed methanesulfonic acid and the carboxyl sites on the croscarmellose sodium disintegrant. Conclusions. Water is thought to act as both a reaction medium and a plasticizer for croscarmellose sodium, facilitating protonation of the carboxyl sites on the disintegrant. This reaction has the potential to occur for any acid salt of a free base. The limiting solubility of delavirdine free base formed in the tablets accounts for much of the decrease in the extent of dissolution. A change in inter-particle bonding can explain the reduction in tablet deaggregation during dissolution.