Solubility Of Phenytoin Research Articles

Machine learning aided drug development: Assessing improvement of drug efficiency by correlation of solubility in supercritical solvent for nanomedicine preparation

In this study, the solubility of phenytoin and the supercritical CO2 (solvent) density were investigated using three different models: Multilayer Perceptron (MLP), NU-SVR, and Poisson Regressor (POR). The models were optimized using the BA algorithm. The inputs for the models were temperature (T) in Kelvin and pressure (P) in bar, while the outputs were the solubility (y) of phenytoin and the CO2 density. For the solubility prediction, the MLP model achieved an impressive R2 score of 0.998 with a MSE of 0.051, a MAE of 0.200, and a MAPE of 0.080. The NU-SVR model also performed well with an R2 score of 0.966, MSE of 1.094, MAE of 0.708, and MAPE of 0.194. The POR model yielded an R2 score of 0.957, MSE of 0.959, MAE of 0.765, and MAPE of 0.337. For the CO2 density prediction, the MLP model achieved an excellent R2 score of 0.998 with an MSE of 75.232, MAE of 5.866, and MAPE of 0.018. The NU-SVR model performed reasonably well with an R2 score of 0.858, MSE of 3853.3, MAE of 49.697, and MAPE of 0.119. The POR model yielded an R2 score of 0.839, MSE of 4012.3, MAE of 52.297, and MAPE of 0.140. These results reveal that the MLP model provides highly reliable forecasts for both the solubility of phenytoin and the CO2 density.

Development of advanced model for understanding the behavior of drug solubility in green solvents: Machine learning modeling for small-molecule API solubility prediction

Determination of small-molecule API (Active Pharmaceutical Ingredient) solubility in solvents is of great importance for drug development in pharmaceutical industry. This study uses machine learning algorithms to predict the solubility of phenytoin drug and density of the solvent at different pressure and temperature. In fact, the solubility of drug (y) and the density of supercritical CO2 (Sc-CO2) were investigated as functions of temperature (T) and pressure (P). Three regression models, namely Gaussian Process Regression (GPR), Gamma Regression (GR), and K-nearest neighbor (KNN) were employed to predict the output variables. To optimize the performance of these models, the Directional Bat Algorithm (dBA) was utilized for hyper-parameter tuning. The outputs demonstrated the accuracy of the developed models in predicting the Sc-CO2 density and solubility of phenytoin. Among the models, GPR exhibited the highest accuracy for both outputs, achieving an R2 value of 0.99 for the solvent density and 0.999 for the solubility. The root mean square error (RMSE) for Sc-CO2 density was approximately 18.37, with an average absolute relative deviation percentage (AARD%) of 4.07% and a maximum error of 37.42. For solubility, the RMSE was approximately 0.087, with an AARD% of 2.29% and a maximum error of 0.150.

Enhancing Oil Solubility of BCS Class II Drug Phenytoin Through Hydrophobic Ion Pairing to Enable High Drug Load in Injectable Nanoemulsion to Prevent Precipitation at Physiological pH With a Potential to Prevent Phlebitis

This work investigates the micellar titration of phenytoin (a weakly acidic drug) with cetyltrimethylammonium hydroxide (CTAH) to form a hydrophobic ion-pair to enhance oil solubility of phenytoin, followed by an effort to formulate nanoemulsion that could potentially prevent precipitation of phenytoin at physiological pH. The ion-pair formulated in nanoemulsion was evaluated for in vitro precipitation during serial dilution at physiological pH. The formation of ion-pair during titration was explained in context of pH-solubility data. The mathematical model successfully integrated ionization and micellization equilibria to reflect on dominant mechanisms for solubilization. The micellar phenomenon during titration was confirmed using Dynamic Light Scattering (DLS). The phase changes of the excess undissolved solids during titration were evident from X-Ray Powder Diffraction (XRPD) and Fourier Transform Infrared Spectroscopy (FTIR). This analysis confirmed the conversion of phenytoin into ionized state and its subsequent ionic interaction with CTAH forming hydrophobic ion-pair complex (HIP). The complete ion pair formation was evident at pHmax (8.8 to 9.2), and its 1:1 stoichiometry was confirmed using HPLC (Phenytoin and CTAH) and H1 NMR, hence could also be called as a lipophilic salt. The ion-pair (salt) was insoluble in water and showed remarkably high partition coefficient (log P) in octanol/water. As characterized by Hot Stage Microscopy (HSM), the melting point of the ion-pair complex was lowered to 150.8⁰C compared to the free acid (> 300οC), this was even further lowered to 81.1 °C when evaluated in castor oil. This led to approximately eight-fold higher solubility of hydrophobic ion pair (HIP) in castor oil compared to the free acid form. The high miscibility in castor oil was suitable to formulate a high drug load injectable dispersed system. This was successfully achieved with lecithin and polysorbate as emulsifiers without leaching drug into continuous phase at pH 7.4. This nanoemulsion (<300 nm, and > +30 mV zeta potential) remain stable when evaluated over a period of one month. A serial dilution study of the nanoemulsion was performed in PBS buffer, microscopic observations suggested no birefringence despite incubation at 25°C for several hours. This result indicated that Phenytoin remained strongly partitioned within dispersed oily phase with a higher drug loading when ion-paired phenytoin was used. The higher drug load could enable a small volume slow bolus injection to meet 50 mg/min or lower delivery rate criteria for Phenytoin in the clinical set up. This provided a pathway to further explore potential injectable nano-emulsion formulations that could alleviate typical phlebitis issue associated with the injectable phenytoin solution administration at physiological pH.

Increasing solubility of phenytoin and raloxifene drugs: Application of supercritical CO2 technology

In the present investigation, the solubility of two drugs i.e., phenytoin and raloxifene, was obtained in supercritical CO2 at various temperatures and pressures. The obtained results were shown that the solubility of phenytoin and raloxifene, based on mole fraction, was between 0.68 × 10−6 to 15.70 × 10−6 and 0.79 × 10−5 to 8.09 × 10−5, respectively. The experimental solubilities data shown the direct influence of pressure on them; nevertheless, the extraction temperature had a different effect. Besides, two mathematical approaches based on thermodynamic models were used to model the phenytoin and raloxifene experimental results. Indeed, solubilities data were predicted using Peng-Robinson equations of state (PR EoS) in conjunction with three famous mixing rules i.e., Kwak-Mansoori (KM) and van der Waals (vdW) type I and II. The obtained results demonstrated the Peng-Robinson equations of state with the Kwak-Mansoori mixing rule predicted the solubilities of phenytoin and raloxifene drugs with more accuracy, especially at higher pressures (in order with an average percent deviation equal to 6.2282 and 5.5715, respectively). Moreover, three density-based correlations, as semi-empirical models, i.e., Garlapati and Madras, Bartle et al. and Mendez-Santiago Teja correlations, were used to model the phenytoin and raloxifene solubilities data. For both drugs, Bartle et al. model showed better performance.

Critical Excipient Properties for the Dissolution Enhancement of Phenytoin.

Solubility-enhancing amorphous solid dispersions can aid in the oral delivery of hydrophobic, poorly soluble drugs. Effective solid dispersion excipients enable high supersaturation drug concentrations over biologically relevant time scales. The critical characteristics of an excipient that allow it to work well in a solid dispersion system are not well understood. We prepared poly(N-isopropylacrylamide), poly(N,N-dimethylacrylamide), and poly(N-hydroxyethylacrylamide) excipients of varying molar mass and examined their ability to improve the aqueous solubility of phenytoin, a Biopharmaceutical Class System Class II drug. Binary and ternary solid dispersions of phenytoin and these excipients, along with hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose, were prepared at 10 wt % drug loading. Dissolution behavior was studied at early time points (<1 min) and over the course of 6 h. Performance of the ternary solid dispersions was largely a function of the concentration of poly(N-isopropylacrylamide) present in micellar structures and the concentration of PNiPAm micelles in the dissolution media. We present several systems that achieved significant improvement of phenytoin solubility over a wide composition range at enhancement factors among the highest seen to date for phenytoin.

Effects of N-methylpyrrolidone and temperature on phenytoin solubility

Temperature and cosolvent are the main parameters to change the aqueous solubility of chemicals and pharmaceuticals. Mathematical models and the parameters of solute and solvents are applied to predict and interpret their solubilization effects. In this study, the solubility of phenytoin in N-methylpyrrolidone (NMP) + water mixtures was determined and the generated data were correlated with the Jouyban-Acree model and its combination with Hansen solubility parameters and Abraham solvation parameters. Moreover, solubilization ratio of phenytoin in 10% of various cosolvents showed a considerable increase and a significant correlation between logarithm of solubilization ratio and hydrogen binding parameters was observed (R2 > 0.9). Despite NMP, temperature could not significantly increase the solubility of phenytoin in NMP + water mixtures against water. The results of this study indicated that NMP is a good solubilizing agent for phenytoin and applied mathematical models could predict solubility of phenytoin with a good accuracy in cosolvent + water mixtures.

Impact of Polymer Excipient Molar Mass and End Groups on Hydrophobic Drug Solubility Enhancement

Solubility-enhancing amorphous solid dispersions are used in the oral delivery of hydrophobic, crystallizable drugs. Effective solid dispersion excipients enable high supersaturation drug concentrations and limit crystallization of the dissolved drug over extended times. We prepared poly(N-isopropylacrylamide)-based excipients of varying molar mass and with various end group identities, and examined their ability to improve the aqueous solubility of the Biopharmaceutical Class System Class II drug, phenytoin. Solid dispersions of these excipients and phenytoin were prepared at 10 wt % drug loading. Performance depended largely on the tendency of the polymer excipient to form micellar aggregates in aqueous buffer. We present several systems that achieved significant improvement of phenytoin solubility, with no indication of drug crystallization over 6 h. This is among the highest enhancement factors seen for phenytoin to date, and the success of these systems is ascribed to the added stability of these “self-micellizing” solid dispersions.

Solubility of phenytoin in aqueous mixtures of ethanol and sodium dodecyl sulfate at 298 K

The solubility of phenytoin in binary mixtures of ethanol + water at 298.2 K in the presence of three different concentrations of sodium dodecyl sulfate (sds) was reported. The Jouyban-Acree model was used for correlating the generated data and the obtained mean relative deviation was 7.3%. When all data points of phenytoin in binary solvents at various sds concentrations were fitted to the model, the obtained mean relative deviation was 10.1%.

A 5% Glucose Infusion Fluid Provokes Significant Precipitation of Phenytoin Sodium Injection via Interruption of the Cosolvent Effect of Propylene Glycol.

The precipitation of phenytoin sodium injection provoked by mixing with infusion fluids renders its use in clinical practice difficult, as rapid intravenous (i.v.) push and i.v. infusion are supposed to be avoided. As some of its aspects remain unclear, this study tried to elucidate this precipitation mechanism. In particular, this study focused on the significant precipitation induced by glucose infusion fluid. The precipitation provoked by 5% glucose infusion fluid was obviously different from the precipitation that accompanied simple pH reduction, in terms of the growth mode and morphology of crystals. In addition, the effect of glucose was partially unrelated to pH reduction. NMR measurements including a two-dimensional nuclear Overhauser effect spectroscopy (2D-NOESY) spectrum indicated the specific interaction between glucose and propylene glycol, which is incorporated into phenytoin sodium injection as a solubilizing agent. These results led to the conclusion that this interaction was crucial for the precipitation of phenytoin, as it diminished the solubilizing effect of propylene glycol, resulting in the enhancement of the crystallization of phenytoin. The determination of phenytoin solubility in aqueous solutions at different pH values revealed that phenytoin incorporated in the admixture could be dissolved completely, as long as the injection was diluted with saline or water. These findings offer a profound insight into the formulation design of phenytoin sodium injection and its use in clinical practice.

Rational design of drug–polymer co-formulations by CO 2 anti-solvent precipitation

The purpose of this study is to investigate the potential of the precipitation with compressed anti-solvent (PCA) process for the design of pharmaceutical drug–polymer co-formulations for solubility enhancement. Co-formulations of the sparingly soluble anticonvulsant phenytoin (5,5-diphenyhydantoin) and the water-soluble polymer excipient poly-(vinyl pyrrolidone) K30 (PVP) have been prepared by PCA. Solutions with drug to polymer ratios between 4:1 and 1:4 have been precipitated at sub- and supercritical conditions (80 bar and 25 °C, and 150 bar and 40 °C) using CO 2 as anti-solvent. Co-formulations with phenytoin concentrations below 40 wt.% were fully amorphous and similar to pure PVP in morphology, while phenytoin was also present in crystalline form in products with higher drug contents. The same threshold concentration was found to apply at both operating conditions. Fully amorphous products did not recrystallize upon one year of storage at ambient conditions. The PCA process could thus be used to maximize the drug loading in stable and fully amorphous solid dispersions of phenytoin in PVP. For the system of consideration, a phenytoin solubility in PVP of about 40 wt.% has been determined.

Solubilization behavior of a poorly soluble drug under combined use of surfactants and cosolvents

The solubilization behavior of a poorly soluble model drug, phenytoin (PHT), under combined use of surfactants (sodium dodecyl sulfate (SDS), Tween 80) and cosolvents (dimethylacetoamide (DMA), ethanol, poly(ethylene glycol) 400 (PEG), glycerol) was examined. The solubility of PHT in the aqueous surfactant solutions increased linearly with increase of the surfactant concentration. The solubility of PHT in water–cosolvent mixtures roughly followed the log-linear model, which is widely accepted to explain the solubilization behavior of poorly soluble compounds in water–cosolvent mixtures, except for the case of glycerol, in which the solubility was minimal at 10% (w/v) of glycerol. When the cosolvents were added to the aqueous surfactant solutions, their effect on the solubility depended on the combination of the surfactant and the cosolvent. The most striking increase in solubility was observed with DMA, regardless of the type of surfactant. When ethanol was added, an increase in the solubility was observed with the Tween 80 solution, while a dramatic decrease was found with the SDS solution. The addition of glycerol or PEG to the surfactant solutions had only a minor impact on the solubility. These solubilization behaviors of PHT in the surfactant–cosolvent mixtures were partially explained by the solubility model introduced in our previous paper [Kawakami, K., Miyoshi, K., Ida, Y., 2004. Solubilization behavior of poorly soluble drugs with combined use of Gelucire 44/14 and cosolvent. J. Pharm. Sci. 93, 1471–1479]. Addition of the cosolvents to the surfactant solutions generally offered only a small advantage from the viewpoint of improving solubility because of the decrease in the solubilization capacity of the micelles.

Formation of phenytoin nanoparticles using rapid expansion of supercritical solution with solid cosolvent (RESS-SC) process

Nanoparticles are of significant importance in drug delivery. Rapid expansion of supercritical solution (RESS) process can produce pure and high-quality drug particles. However, due to extremely low solubility of polar drugs in supercritical CO 2 (sc CO 2), RESS has limited commercial applicability. To overcome this major limitation, a modified process rapid expansion of supercritical solution with solid cosolvent (RESS-SC) is proposed which uses a solid cosolvent. Here, the new process is tested for phenytoin drug using menthol solid cosolvent. Phenytoin solubility in pure sc CO 2 is only 3 μmol/mol but when menthol solid cosolvent is used the solubility is enhanced to 1302 μmol/mol, at 196 bar and 45 °C. This 400-fold increase in the solubility can be attributed to the interaction between phenytoin and menthol. Particle agglomeration in expansion zone is another major issue with conventional RESS process. In proposed RESS-SC process solid cosolvent hinders the particle growth resulting in the formation of small nanoparticles. For example, the average particle size of phenytoin in conventional RESS process is 200 nm whereas, with RESS-SC process, the average particle size is 120 nm, at 96 bar and 45 °C. Similarly at 196 bar and 45 °C, 105 nm average particles were obatined by RESS and 75 nm average particles were obtained in RESS-SC process. The particles obtained were characterized by Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), dynamic light scattering (DLS) and differential scanning calorimetery (DSC) analyses. Phenytoin nanoparticle production rate in RESS-SC is about 400-fold more in comparision to that in RESS process.

Development and Testing of an Improved Parenteral Formulation of Phenytoin Using 2-Hydroxypropyl-β-cyclodextrin

The objective of this study was to increase the solubility of phenytoin by complexing it with varying concentrations of 2-hydroxypropyl-β-cyclodextrin (HPBCD) and create an entirely aqueous formulation with a pH significantly closer to physiologic pH (7.4). The phenytoin–HPBCD complexation was characterized using phase-solubility analysis at HPBCD concentrations ranging from 10 to 50% w/v over the pH range of 7.4–11.0. The two most promising formulations, i.e., a formulation consisting of 40% HPBCD at pH 10.4, and a second formulation consisting of 20% HPBCD at pH 11.0, were selected for further study. Both formulations were entirely aqueous and had a significantly decreased pH compared to the original commercial formulation (Parke-Davis, pH 12.0). These formulations also exhibited a significantly decreased tendency to precipitate in vitro. The tissue irritation potential of the 20% w/v HPBCD formulation at pH 11.0 was found to be reduced considerably compared to the commercial injection in a BALB/c mouse model.

Increased Shelf-Life of Fosphenytoin: Solubilization of a Degradant, Phenytoin, through Complexation with (SBE)7M-β-CD

Fosphenytoin, a water-soluble prodrug of phenytoin, degrades primarily to phenytoin at pH values <8 during long term storage; phenytoin readily precipitates when formed from fosphenytoin due to its limited aqueous solubility. The objective of this study was to develop stable formulations of fosphenytoin in the pH range of 7.4–8.0 by inhibiting the phenytoin precipitation through complexation with a parenterally safe cyclodextrin, (SBE)7m-β-CD. Phase solubility studies at 25°C revealed that phenytoin could be effectively solubilized by (SBE)7m-β-CD both in the presence and absence of 80.6mg/mL fosphenytoin (as its dihydrate). The binding constants for the phenytoin/cyclodextrin complex were found to be 1073 and 792M−1 at pH7.4 and pH8.0, respectively. Because of the competitive inclusion between fosphenytoin and phenytoin with (SBE)7m-β-CD, the extent of solubilization of phenytoin was lower, as expected, in the presence of fosphenytoin than in the absence of fosphenytoin, even though the binding constants for the fosphenytoin/cyclodextrin complex were relatively small (41–45M−1). Initial rates were used to follow the production of phenytoin from fosphenytoin. Zero-order kinetics were observed under all conditions investigated. Phenytoin production rates were followed at 25, 37, and 50°C in the presence of 0.03 or 0.06M (SBE)7m-β-CD. It was projected from the solubility of phenytoin and the kinetic information that fosphenytoin shelf lives as high as nine years at 25°C and pH7.4 in the presence of 60mM of (SBE)7m-β-CD might be possible while longer shelf lives might be possible at pH8.

Prevention of precipitation of phenytoin in an infusion fluid by hydroxypropyl beta-cyclodextrin.

Injection of phenytoin is often diluted with infusion fluids before administration, which may lead to precipitation of the drug due to changes in pH and/or vehicle. It is not possible to add cyclodextrins to the original injections to prevent precipitation of the drug, because the quantities required would be impractical (>100% w/v). However, from a knowledge of the solubility of phenytoin in cyclodextrin solutions, it is possible to add sufficient amounts of a soluble cyclodextrin to infusion fluids to maintain the solubility of phenytoin after the original injection is diluted to clinical concentrations in the fluid. From solubility measurements, theoretical amounts of hydroxypropyl beta-cyclodextrin (HPCD), sufficient to prevent precipitation of phenytoin, were added to 0.9% w/v sodium chloride solution, adjusted to pH 7.0. Phenytoin injection was diluted to clinical concentrations in the cyclodextrin/NaCl solutions. The mixtures, together with analogous mixtures containing phenytoin, but no HPCD, were stored at 25 degrees C for 3 days. In the presence of the cyclodextrin no precipitates of phenytoin were observed, but in its absence an immediate massive precipitation of phenytoin occurred. This is a flexible method for using soluble cyclodextrins to prevent precipitates of drugs in infusion fluids, provided the cyclodextrin used is not toxic.

Improved dissolution and bioavailability of phenytoin by sulfobutylether- β-cyclodextrin ((SBE) 7m- β-CD) and hydroxypropyl- β-cyclodextrin (HP- β-CD) complexation

The inclusion complexation of phenytoin with charged and neutral water-soluble cyclodextrins (CDs), (SBE) 7m- β-CD and HP- β-CD, was studied in order to improve the low aqueous solubility and incomplete oral bioavailability of phenytoin. Effects of CDs on the aqueous solubility of phenytoin were determined by phase-solubility method at pH 7.4 and 11.0. Solubility of phenytoin increased as a function of CD concentration, showing A L type diagrams for both (SBE) 7m- β-CD and HP- β-CD which indicate a formation of 1:1-complexes. Solid inclusion complexes of phenytoin with (SBE) 7m- β-CD and HP- β-CD were prepared by freeze-drying. Dissolution rate of phenytoin was increased with inclusion complexes as well as with phenytoin/HP- β-CD physical mixture in vitro. Also the freeze-drying of phenytoin tended to enhance the dissolution of phenytoin in vitro. However, plain phenytoin (300.0 mg) pharmacokinetics after oral administration as a crystal form and as a freeze-dried form were comparable in dogs. CD-based formulations of phenytoin increased peak plasma concentration of phenytoin about 1.6-fold and bioavailability (AUC 0–24 h) of phenytoin about 2-fold compared to plain phenytoin. Oral pharmacokinetics were not statistically different among various CD formulations. This study indicates that increased bioavailability of phenytoin in the presence of CDs was due to an increased extent of drug dissolution.

Assessment of a hydroalcoholic surfactant solution as a medium for the dissolution testing of phenytoin

A buffered hydroalcoholic surfactant solution has been developed as a dissolution medium for phenytoin based on a statistically designed solubility study. A compromise between acceptable composition (relatively low additive concentrations and physiologically relevant pH), sufficient phenytoin solubility at a pH lower than the drug's pKa (8.3) and potential discrimination power was considered in the design. The medium selected was a pH 6.8 phosphate buffer containing 12% alcohol and 0.4% Tween 80. Both phenytoin and phenytoin sodium bulk powder dissolved at a higher rate in the test medium relative to water (the USP medium for phenytoin sodium capsules). The medium proved sensitive to dissolution differences between phenytoin sodium samples with different content of the acid form. A linear relationship was obtained between the acid content and percent dissolution at 30 min for these samples. Further, the test medium could detect the reduction in dissolution of a phenytoin sodium sample subjected to storage conditions (1 month at 40°C and 75% R.H.) allowing partial conversion to the acid form. From a practical standpoint, these findings may be useful in assessing the in vitro performance of both phenytoin and phenytoin sodium formulations and their dissolution stability.

Estimation of the increase in solubility of drugs as a function of bile salt concentration.

The objective of this study was to develop a model to predict the extent to which bile salts can enhance the solubility of a drug, based on the physicochemical properties of the compound. The ability to predict bile salt solubilization of poorly soluble drugs would be a key component in determining which drugs will exhibit fed vs. fasted differences in drug absorption. A correlation between the logarithm of the octanol/water partition coefficient [log P] of six steroidal compounds and their solubilities in the presence of various concentrations of sodium taurocholate at 37 degrees C, log [SR] = 2.234 + 0.606 log [P] (r2 = 0.987) where SR is the ratio of the stabilization capacity of the bile salt to the solubilization capacity of water for the drug, was used to predict the solubility of the compounds in presence of sodium taurocholate were then measured. The predicted solubilities were within 10% of the experimentally observed solubilities for griseofulvin, cyclosporin A and pentazocine. The model overpredicted the solubility of phenytoin and diazepam in 15 mM sodium taurocholate solution by a factor of 1.33 and 1.62 respectively. The expected increase in solubility as a function of bile salt concentration can be estimated on the basis of the partition coefficient and aqueous solubility of the compound.

Determination of the position of the ester bond in a micellar prodrug of phenytoin

It was previously determined that the nearly 200-fold increase in the observed precipitation times of aqueous prodrug solutions of 3-( N, N-dimethylglycyloxymethyl)-5,5-diphenyl hydantoin methane sulphonate (DDMS) was a result of a decrease in the rate of hydrolysis of the prodrug as well as an increase in the solubility of phenytoin in the presence of DDMS. The formation of a series of associative species by the prodrug are probably responsible for the changes observed in solubility and the rate of hydrolysis. Final proof of the presence of micellar prodrug species was obtained with NMR studies. The major upfield shift shown by the protons of the phenyl groups substantiated the hypothesis that the hydrophobic groups of the prodrug molecules formed the hydrophobic core of the micelles, which enabled the inclusion of the phenytoin, which is hydrophobic, and thereby causes the phenytoin to be solubilized. The NMR results also showed that the labile ester binding of the prodrug was submerged into the micelle which could explain the decrease in the rate of hydrolysis of the prodrug that was previously reported.

The determination of the amphiphilic properties of a prodrug (DDMS) of phenytoin in aqueous media

During a previous study it was established that a change in the intrinsic solubility of phenytoin in the presence of its prodrug (DDMS), and a change in the rate of hydrolysis of the prodrug in the presence of higher concentrations thereof, could account for increases in precipitation times of aqueous prodrug solutions. The 50% reduction in the rate of hydrolysis observed at higher prodrug concentrations and the 45-fold increase in the solubility of phenytoin at therapeutic levels of the prodrug were both attributed to the observed increase in precipitation times. In an effort to explain the observed changes in solubility and kinetics a series of experiments were performed to determine the extent of the formation of amphiphilic structures in aqueous media. The presence of associative species in aqueous prodrug solutions was established by tensiometry, conductivity and dynamic light scattering experiments. Electron microscopy showed spherical shapes with sizes which compared favourably with the sizes found with the laser and Kratel particle counter techniques.