Study of phase behavior of poly(ethylene glycol)-polysorbate 80 and poly(ethylene glycol)-polysorbate 80-water mixtures.

Mixtures of poly(ethylene glycols) (PEGs) with polysorbate 80 are often used to dissolve poorly water-soluble drugs in dosage forms, where polysorbate 80 helps either in enhancing dispersion or in inhibiting precipitation of drugs once the solution is mixed with water. Binary phase diagrams of polysorbate 80 with several low molecular weight PEGs and a ternary phase diagram of polysorbate 80 with PEG 400 and water are presented. Two phases were observed in the binary mixtures when the concentration of PEG 200, PEG 300, PEG 400, or PEG 600 was >55%(w/w). The miscibility of the binary mixtures increases with an increase in temperature; the upper consolute temperatures of PEG 200-polysorbate 80, PEG 300-polysorbate 80, PEG 400-polysorbate 80, and PEG 600-polysorbate 80 mixtures were 100, 85, 75, and 40 degrees C, respectively. The upper consolute temperature of PEG 1000-polysorbate 80 could not be determined because the melting temperature of the mixtures is approximately 40 degrees C and the consolute temperature appeared to be less than this temperature. The decrease in upper consolute temperature with an increase in PEG molecular weight indicated a greater miscibility of the two components. In the ternary system, phase separation of polysorbate 80 was observed when the concentration of PEG 400 was >50-60 % (w/w), possibly because of the high exclusion volume of PEG 400.

Moisture sorption behavior of selected bulking agents used in lyophilized products.

To develop a rational approach for the formulation of lyophilized products, six bulking agents commonly used in freeze-dried formulations were lyophilized under identical conditions, and their moisture sorption behavior, before and after lyophilization, were determined as a function of relative humidity at 25 degrees C. The bulking agents evaluated were mannitol, anhydrous lactose, sucrose, D(+)-trehalose, dextran 40 and povidone (PVP K24). The materials were also characterized for their crystal and thermal properties by powder X-ray diffraction, DSC and TG after exposure to various relative humidity conditions. Mannitol was crystalline and non-hygroscopic both before and after lyophilization with total moisture contents of 0.1 to 0.3% w/w between 10 and 60% RH. Anhydrous lactose, sucrose and trehalose were crystalline prior to lyophilization with moisture contents of 0.86, 0.15 and 9.2%, respectively, and the crystalline materials were relatively non-hygroscopic. Upon lyophilization, they converted to the amorphous form and had moisture contents of 1.6, 2.5 and 1.2%, respectively. The amorphous materials sorbed moisture rapidly upon exposure to increasing relative humidity conditions. The amorphous lactose converted to its crystalline hydrate form at 55% RH after sorption of an additional 10% moisture. This conversion to the crystalline hydrate form was accompanied by desorption of practically all the moisture sorbed by the amorphous form. Similarly, lyophilized sucrose converted to its crystalline form after the sorption of additional 4.5% moisture at 50% RH, and the lyophilized trehalose sorbed additional 10% moisture prior to its conversion to a crystalline hydrate form at 50% RH. Dextran and povidone were amorphous and hygroscopic both before and after lyophilization and they sorbed as much as 10-20% moisture at 50% RH. It is well established that different drugs, especially proteins, need different levels of moisture for optimal stability. The results of the present study show that moisture contents of lyophilized cakes may be varied and optimized by the selection of suitable excipients.

Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs.

Although there was a great interest in solid dispersion systems during the past four decades to increase dissolution rate and bioavailability of poorly water-soluble drugs, their commercial use has been very limited, primarily because of manufacturing difficulties and stability problems. Solid dispersions of drugs were generally produced by melt or solvent evaporation methods. The materials, which were usually semisolid and waxy in nature, were hardened by cooling to very low temperatures. They were then pulverized, sieved, mixed with relatively large amounts of excipients, and encapsulated into hard gelatin capsules or compressed into tablets. These operations were difficult to scale up for the manufacture of dosage forms. The situation has, however, been changing in recent years because of the availability of surface-active and self-emulsifying carriers and the development of technologies to encapsulate solid dispersions directly into hard gelatin capsules as melts. Solid plugs are formed inside the capsules when the melts are cooled to room temperature. Because of surface activity of carriers used, complete dissolution of drug from such solid dispersions can be obtained without the need for pulverization, sieving, mixing with excipients, etc. Equipment is available for large-scale manufacturing of such capsules. Some practical limitations of dosage form development might be the inadequate solubility of drugs in carriers and the instability of drugs and carriers at elevated temperatures necessary to manufacture capsules.

Selection of solid dosage form composition through drug-excipient compatibility testing.

A drug-excipient compatibility screening model was developed by which potential stability problems due to interactions of drug substances with excipients in solid dosage forms can be predicted. The model involved storing drug-excipient blends with 20% added water in closed glass vials at 50 degrees C and analyzing them after 1 and 3 weeks for chemical and physical stability. The total weight of drug-excipient blend in a vial was usually kept at about 200 mg. The amount of drug substance in a blend was determined on the basis of the expected drug-to-excipient ratio in the final formulation. Potential roles of several key factors, such as the chemical nature of the excipient, drug-to-excipient ratio, moisture, microenvironmental pH of the drug-excipient mixture, temperature, and light, on dosage form stability could be identified by using the model. Certain physical changes, such as polymorphic conversion or change from crystalline to amorphous form, that could occur in drug-excipient mixtures were also studied. Selection of dosage form composition by using this model at the outset of a drug development program would lead to reduction of "surprise" problems during long-term stability testing of drug products.

Effect of humidity-dependent changes in crystal structure on the solid-state fluorescence properties of a new HMG-CoA reductase inhibitor.

It has been shown previously that the disodium salt of a new HMG-CoA reductase inhibitor (SQ-33600) is capable of existing as a number of hydrate species [1]. Three crystalline solid hydrates and one liquid crystalline phase have been identified, each having a definite stability over a defined range of humidity. These forms have been found to exhibit varying fluorescence properties in their respective solid states, with differences in bandshapes and intensities being noted for each. These spectral variations have been correlated with the known pseudopolymorphism of the compound.

Solid-state NMR and IR for the analysis of pharmaceutical solids: polymorphs of fosinopril sodium.

The two polymorphic modifications of fosinopril sodium have been characterized as to their differences in melting behaviour, powder X-ray diffraction patterns, Fourier transform infrared spectra (FTIR), and solid-state 31P- and 13C-NMR spectra. The polymorphs were found to be enantiotropically related based upon melting point, heat of fusion, and solution mediated transformation data. Analysis of the solid-state FTIR and 13C-NMR data indicated that the environment of the acetal side chain of fosinopril sodium differed in two polymorphs, and that there might be cis-trans isomerization about the C6-N peptide bond. These conformational differences are postulated as the origin of the observed polymorphism.

Influence of pH on release of phenytoin sodium from slow-release dosage forms.

Physicochemical factors influencing the release of phenytoin sodium from slow-release dosage forms were studied. Some of these factors were solubility and intrinsic dissolution rate as functions of pH, type of dosage form, pH of dissolution medium used, and conversion of the sodium salt to free acid (phenytoin). The innovator's product, Extended Phenytoin Sodium Capsule (Dilantin Kapseal, 100 mg, Parke-Davis), and two experimental formulations (one nondisintegrating tablet containing polymeric materials and the other a solid dispersion in an erodible matrix) served as the slow-release dosage forms. The sodium salt converts to practically insoluble phenytoin in the gastrointestinal pH range of 1 to 8. Due to such a conversion inside or at the surface of slow-release dosage forms, the release of drug in this pH range was incomplete. The extent of drug release also varied with the type of formulation used. In contrast, complete dissolution could be obtained in water because the pH of the medium gradually rose from approximately 6 to approximately 9.2 where the drug solubility was higher. Although several phenytoin sodium products might have similar dissolution rates in water, the extents of drug release under gastrointestinal pH conditions (pH 1-8) could differ greatly, thus supporting the Food and Drug Administration recognition that the similarity in dissolution profiles in water does not assure that the products are bioequivalent. The reported lower steady-state level of phenytoin in human plasma following oral administration of a slow-release dosage form may be related to incomplete drug release.

Structural properties of polyethylene glycol-polysorbate 80 mixture, a solid dispersion vehicle.

The structural properties of the mixtures of polysorbate 80 with various polyethylene glycols (PEG), viz., PEG 1000, PEG 1450, PEG 3350, and PEG 8000, have been investigated by powder X-ray diffraction (XRD) and differential scanning calorimetric studies. These mixtures may be used as solid dispersion vehicles to insure complete dissolution of poorly water-soluble drugs. Although polysorbate 80 is a liquid at room temperature, the PEG-polysorbate 80 mixtures with up to 75% (w/w) polysorbate 80 were solid. The XRD studies revealed that the crystal structures (d-spacings) of the PEGs (M(r) 1000, 1450, 3350, and 8000) did not change with increasing amounts of polysorbate 80 in the mixture. The intensities of the XRD peaks, however, varied approximately in proportion to the concentration of PEG present. Similarly, the differential scanning calorimetric studies showed that the melting behavior of a PEG-polysorbate 80 mixture was similar to that of the PEG used. The lowering of the mp of a particular PEG due to the presence of 50% (w/w) polysorbate 80 in the mixture was < 6 degrees C, and the decrease in mp was < 12 degrees C in the presence of 75% (w/w) polysorbate 80. When enthalpies of fusion of the mixtures were normalized for the amounts of PEGs present, they were similar to those of pure PEGs. These results indicate that the crystalline structure of PEG in a PEG-polysorbate 80 mixture is substantially the same as that of the pure PEG, and that polysorbate 80 is incorporated into the amorphous region of PEG solid structure.

Relative lipophilicities and structural-pharmacological considerations of various angiotensin-converting enzyme (ACE) inhibitors.

Lipophilicities of seven structurally diverse angiotensin-converting enzyme (ACE) inhibitors, viz., captopril, zofenoprilat, enalaprilat, ramiprilat, lisinopril, fosinoprilat, and ceronapril (SQ29852), were compared by determining their octanol-water distribution coefficients (D) under physiological pH conditions. The distribution co-efficients of zofenopril, enalapril, ramipril and fosinopril, which are the prodrug forms of zofenoprilat, enalaprilat, ramiprilat, and fosinoprilat, respectively, were also determined. Attempts were made to correlate lipophilicities with the reported data for oral absorption, protein binding, ACE inhibitory activity, propensity for biliary excretion, and penetration across the blood-brain barrier for these therapeutic entities. Better absorption of prodrugs compared to their respective active forms is in agreement with their greater lipophilicities. Captopril, lisinopril, and ceronapril are orally well absorbed despite their low lipophilicities, suggesting involvement of other factors such as a carrier-mediated transport process. Of all the compounds studied, the two most lipophilic ACE inhibitors, fosinoprilat and zofenoprilat, exhibit a rank-order correlation with respect to biliary excretion. This may explain the dual routes of elimination (renal and hepatic) observed with fosinoprilat in humans. The more lipophilic compounds also exhibit higher protein binding. Both the lipophilicity and a carrier-mediated process may be involved in penetration of some of these drugs into brain. For structurally similar compounds, in vitro ACE inhibitory activity increased with the increase in lipophilicity. However, no clear correlation between lipophilicity and ACE inhibitory activity emerged when different types of inhibitors are compared, possibly because their interactions with enzymes are primarily ionic in nature.

Interaction of metronidazole with antibiotics containing the 2-aminothiazole moiety.

The mechanism of possible incompatibility between commercially available metronidazole parenteral solutions and the injectable aztreonam leading to the development of pink color in their intravenous admixtures was studied. It was demonstrated that nitrite ions may be produced in metronidazole solutions at the time of preparation or during storage by the effects of temperature and light. Under acidic pH conditions of admixtures the aminothiazole moiety of aztreonam was diazotized by the nitrite ion contributed by metronidazole solutions. The diazotized molecule, in turn, reacted with another aztreonam molecule by diazo-coupling. The resultant pink-colored product was isolated by chromatography and its structure was determined by mass spectral and NMR analyses. Other beta-lactam antibiotics containing the 2-aminothiazole moiety also react in acidic media in a similar manner.

Relative lipophilicities, solubilities, and structure-pharmacological considerations of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors pravastatin, lovastatin, mevastatin, and simvastatin.

The apparent octanol-water partition coefficients (Po/w) and aqueous solubilities for four 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors [pravastatin, lovastatin (mevinolin), mevastatin (compactin), and simvastatin (synvinolin)] were compared. Pravastatin is highly hydrophilic compared with lovastatin, mevastatin, or simvastatin. Pravastatin is clinically used as the active hydroxy acid, while the other three compounds are administered as prodrug lactones which, over a period of time, convert in vivo to their respective active hydroxy acid forms. The order of the Po/w values of the hydroxy acid forms was pravastatin much less than mevastatin less than lovastatin less than simvastatin at each pH evaluated, with approximate ratios of 1:25:75:200, respectively. The relative order and the ratios of partition coefficients for the lactone forms were similar to those for the hydroxy acid forms. In addition, lovastatin, mevastatin, and simvastatin are virtually insoluble in water, with solubility values ranging from 0.0013 to 0.0015 mg/mL at 23 degrees C. In comparison, pravastatin is hydrophilic, as demonstrated by the greater than 100-fold greater solubility of its lactone form (0.18 mg/mL). The greater hydrophilicity of pravastatin may explain its reported lower permeation into nonhepatic cells and the selectivity with respect to inhibition of cholesterol synthesis.

Optimization of cosolvent concentration and excipient composition in a topical corticosteroid solution.

Physicochemical factors involved in the development of a topical solution of a novel corticosteroid, tipredane (1), are described. A cosolvent system consisting of polyethylene glycol 400 (PEG 400), propylene glycol, and water was used to dissolve the concentration (0.1% w/w) of 1 required for the formulation. The solvent mixture was also nonirritating to the skin. Buffering agent, antioxidant, and metal-chelating agent were required to stabilize the drug. Solubilities of hydrophilic and lipophilic excipients were ensured by careful adjustment of their concentrations, as well as that of PEG 400. Two formulations, one containing potassium citrate and the other tromethamine as the buffering agents, were identified. Upon storage, sodium metabisulfite, an antioxidant used in the formulation, oxidized to form K2SO4 in the formulation containing potassium citrate. Potassium citrate decreased the solubility and resulted in the precipitation of K2SO4 by exerting a common ion effect. Lowering of the concentrations of potassium citrate, sodium metabisulfite, and PEG 400 ensured the solubility of K2SO4 formed. There was no such precipitation of K2SO4 in the formulation buffered with tromethamine, thus indicating that tromethamine is a good buffering agent in cosolvent systems.

Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water-soluble drug from solid dispersions.

Solid dispersions of a poorly water-soluble drug [REV 5901; alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; 1] in an amphiphilic vehicle [Gelucire 44/14; 2] and in polyethylene glycol (PEG) 1000, PEG 1450, and PEG 8000 were prepared. The vehicle 2 was a mixture of hydrogenated fatty acid esters with a mp of 44 degrees C, and had a HLB value of 14. Compound 1 was dissolved or dispersed in molten vehicles at elevated temperatures. The pulverization and compression of solid dispersions were avoided by encapsulating the hot solutions directly into hard gelatin capsules. At room temperature, the dispersions solidified forming plugs inside the capsules. On storage, greater than 180 mg of 1 remained dissolved per gram of vehicle, while the excess drug formed fine crystals (less than 20 micron). When mixed with water, the dissolved drug separated as a metastable liquid. Due to the surfactant property of 2, the oily form of 1 that separated from this vehicle formed an emulsified system with a globular size of less than 1 micron, while greater than 80% of 1 that separated from the other three formulations coalesced to form large oily masses. As a result of the large difference in surface area, the dissolution rate of 1 in simulated gastric fluid from capsules containing 2 was much higher than that of a PEG-based formulation. The bioavailability (AUC) of 1 in dogs from capsules containing 2 was also higher than that from PEG 1000-based capsules.

Physicochemical basis of increased bioavailability of a poorly water-soluble drug following oral administration as organic solutions.

The physicochemical basis of improvement of the bioavailability of a poorly water-soluble drug [REV 5901; alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; 1] after oral administration as organic solutions was investigated. The drug, which exists in solid and metastable liquid forms, had a pKa value of 3.7 and a solubility of approximately 0.002 mg/mL in water (pH approximately 6) at 37 degrees C. It had appreciable aqueous solubility only at pH values less than 2. The dissolution rate of 1 at pH values greater than 3 was practically zero. On dilution of the water-miscible organic solutions (polyethylene glycol 400 and polysorbate 80) of 1 with aqueous media, the drug instantaneously formed saturated solutions and the excess drug separated as emulsified oily globules. The dispersibility of the globules improved in the presence of surfactants. The average globule size of the oily form of 1 was 1.6 micron or less, as compared with a particle size of 5-10 microns for the solids. Thus, a high surface area of 1 was obtained after oral intake of water-miscible organic solutions. Although 1 was practically insoluble under intestinal pH conditions, its solubility was greatly increased in the presence of bile salts, lecithin, and lipid-digestion mixtures. The high surface area of 1 separating from organic solutions would facilitate its dissolution rate in the presence of biological surfactants and lipids and, therefore, would increase its bioavailability.

Common ion effect on solubility and dissolution rate of the sodium salt of an organic acid.

The solubility and the dissolution rate of the sodium salt of an acidic drug (REV 3164; 7-chloro-5-propyl-1H,4H-[1,2,4]triazolo[4,3-alpha]quinoxaline-1,4-dione) decreased by the effect of common ion present in aqueous media. The solubility of the sodium salt of REV 3164 in a buffered medium was much lower than that in an unbuffered medium. Also, the presence of NaCl decreased its solubility in water. The apparent solubility product (K'sp) of the salt, however, did not remain constant when the concentration of NaCl was changed. A decrease in K'sp value with the increase in NaCl concentration was observed; for example, the K'sp values at 0 and 1 M NaCl were 7.84 X 10(-4) and 3.94 X 10(-4) M2, respectively. Even when corrected for the effect of ionic strength, the solubility product decreased. This decrease in the solubility product in the presence of NaCl indicated a decrease in the degree of self-association (increase in activity coefficient) of the drug in aqueous media.

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)

Effect of thermal history on the glassy state of indapamide.

The effects of thermal history, e.g. cooling rate, annealing, etc., on the thermal behaviour of indapamide glass were determined by differential scanning calorimetry (DSC). The glass was prepared by heating indapamide crystals (m.p. 162 degrees C) to 180 degrees C, and then cooling the melt to room temperature. The glass transition temperature (Tg) of the material was 98 degrees C. An endotherm, due to thermal relaxation of the glass, was observed in the DSC thermogram when indapamide glass was prepared by slow cooling or was annealed isothermally at a temperature below Tg. Such enthalpy relaxation may be observed during ageing of pharmaceutical glasses and might influence their physico-chemical properties.