盐酸氨溴索平衡溶解度和表观油水分配系数的测定

目的 测定盐酸氨溴索在多个pH值介质中的平衡溶解度及表观油水分配系数,为其制剂研究与处方筛选提供依据。方法 采用紫外分光光度法测定盐酸氨溴索在水及10种有机溶剂中的平衡溶解度,通过盐酸氨溴索分配平衡后在油相和水相中的浓度比,计算其油水分配系数。结果 盐酸氨溴索在各pH值介质中的平衡溶解度均较高,尤其是在蒸馏水以及pH值为2.0、5.8的缓冲液中,平衡溶解度分别为26.04、27.91、28.24 mg/mL;油水分配系数在pH7.4时最高,lgP为1.78。结论 盐酸氨溴索的平衡溶解度及表观油水分配系数与各介质的pH值有关,且可推测其在人体内的胃肠吸收良好,有较好的应用价值。     

Intrinsic Solubility Estimation and pH-Solubility Behavior of Cosalane (NSC 658586), an Extremely Hydrophobic Diprotic Acid

Purpose. The selection of cosalane (NSC 658586) by the National Cancer Institute for further development as a potential drug candidate for the treatment of AIDS led to the exploration of the solubility behavior of this extremely hydrophobic drug, which has an intrinsic solubility (S₀) approaching 1 ng/ml. This study describes attempts to reliably measure the intrinsic solubility of cosalane and examine its pH-solubility behavior. Methods. S₀ was estimated by 5 different strategies: (a) direct determination in an aqueous suspension; (b) facilitated dissolution; (c) estimation from the octanol/water partition coefficient and octanol solubility; (d) application of an empirical equation based on melting point and partition coefficient; and (e) estimation from the hydrocarbon solubility and functional group contributions for transfer from hydrocarbon to water. Results. S₀ estimates using these five methods varied over a 5 × 10⁹-fold range. Method (a) yielded the highest values, two-orders of magnitude greater than those obtained by method (b) (facilitated dissolution, 1.4 ± 0.5 ng/ml). Method (c) gave a value 20-fold higher while that from method (d) was in fair agreement with that from facilitated dissolution. Method (e) yielded a value several orders-of-magnitude lower than other methods. A molecular dynamics simulation suggests that folded conformations not accounted for by group contributions may reduce cosalane's effective hydrophobicity. Ionic equilibria calculations for this weak diprotic acid suggested a 100-fold increase in solubility per pH unit increase. The pH-solubility profile of cosalane at 25°C agreed closely with theory. Conclusions. These studies highlight the difficulty in determining solubility of very poorly soluble compounds and the possible advantage of the facilitated dissolution method. The diprotic nature of cosalane enabled a solubility enhancement of >10⁷-fold by simple pH adjustment.     

Prediction of Intestinal Drug Absorption Properties by Three-Dimensional Solubility Parameters

Purpose. The purpose of this study was to investigate the use of solubility parameters for the prediction of gastrointestinal absorption sites and absorption durations of drugs. Methods. Three-dimensional solubility parameters of drug substances were calculated using an advanced parameter set based on the group contribution methods of Fedors and Van Krevelen/Hoftyzer. The results of the calculations were illustrated via Bagley diagram and related to absorption data reported in the literature. Results. Solubility parameters of drugs which are known to be absorbed over a long period in human's digestive tract were found in a limited area within the Bagley diagram. From the three-dimensional solubility parameters of these substances, a region for optimal absorption with the centre coordinates _v = 20.3 (J cm^–3)^0.5 and _h = 11.3 (J cm^–3)^0.5 could be derived. Drugs with absorption sites along the whole gastrointestinal tract were found in this area. Drugs which are preferably absorbed from upper parts of the intestine are located in another typical region with partial solubility parameters _h of more than 17 (J cm^–3)^0.5. Conclusions. The method which is presented in this paper appears as a simple but effective method to estimate the absorption behaviour of new substances in drug research and development.     

Solubility Behavior of Narcotic Analgesics in Aqueous Media: Solubilities and Dissociation Constants of Morphine,Fentanyl, and Sufentanil

The pH dependence of the aqueous solubility of morphine, fentanyl, and sufentanil was investigated at 35°C. Dissociation constants and corresponding pK _a values of the drugs were obtained from measured free-base solubilities (determined at high pH's) and the concentrations of saturated solutions at intermediate pH's. Morphine, fentanyl, and sufentanil exhibited pK _a values of 8.08, 8.99, and 8.51, respectively. Over the pH range of 5 to 12.5 the apparent solubilities are determined by the intrinsic solubility of the free base plus the concentration of ionized drug necessary to satisfy the dissociation equilibrium at a given pH. Consequently, the drug concentrations of saturated aqueous solutions fall off precipitously as the pH is raised and ionization is suppressed. Further, at low pH's the aqueous solubility of morphine increased in a linear fashion with increases in the molar strength of citric acid which was added to acidify the medium, suggesting the formation of a soluble morphine–citrate complex.     

Effect of Ultrasound Application on Skin Metabolism of Prednisolone 21-Acetate

Purpose. The effect of ultrasound on skin penetration and metabolism of prednisolone (PN) and prednisolone 21-acetate (PNA) was investigated in the hairless mouse skin in vitro. Methods. The abdominal skin excised freshly was pretreated under different ultrasound intensities (4.32, 2.88, and 1.50 W/cm²) for 10, 30, and 60 min. The penetration/metabolism rate of PNA and its metabolite (PN) was then measured using a side-by-side diffusion cell. Results. The skin penetration of PN was enhanced by the ultrasound pretreatment. This enhancement was attributed to the decrease in the stratum corneum barrier capacity by ultrasound energy. The steady-state appearance rate of PN following the skin bioconversion of PNA decreased appreciably with increasing the product of the duration of pretreatment (D_p, min) and the intensity of ultrasound applied (I_u W/cm²). When the product value was less than 40 W/cm² min, the steady-state appearance rate of the PN hardly increased in spite of the penetration enhancement of PNA. Conclusions. These findings indicated a possible deactivation of the skin enzymes by ultrasound energy.     

Cosolvency and Cosolvent Polarity

The solubilities of three poorly soluble drugs, phenytoin, benzocaine, and diazepam, in cosolvent– water mixtures have been previously shown to be approximated by the log-linear solubility equation; log (S _m/S _w) = f, where S _m and S _w represent the solubilities of the drug in the solvent mixture and water, respectively, f is the volume fraction of cosolvent, and is the slope of a plot of log (S _m/S _w) vs f. In this study, the slopes, , of the solubility plots were related to indexes of cosolvent polarity including the dielectric constant, solubility parameter, surface tension, interfacial tension, and octanol–water partition coefficient. Those polarity indexes that reflect the cohesive properties of the solvents such as the solubility parameter and interfacial tension resulted in the highest correlations with the slope, . The hydrogen bonding ability of the neat cosolvent, expressed as the density of proton donating groups (HBD) or acceptor groups (HBA), was also found to be highly correlated with . Additional relationships derived from theories involving solubility parameters and interfacial tension provide improved correlations between the cosolvent polarity and . These results and analysis provide the basis for the estimation from physicochemical parameters of the appropriate type and amount of cosolvent needed to solubilize nonpolar drugs.     

Effect of Sodium Bicarbonate Amount on In Vitro Indomethacin Release from Self-Setting Carbonated-Apatite Cement

Purpose. In the present study, to develop a drug delivery system with higher bioacitivity in hard tissues by using the self-setting bioactive carbonate apatite cement, we have investigated the effects of sodium bicarbonate content on thein vitro drug release from a self-setting bioactive carbonate apatite cement containing indomethacin (IMC). Methods. The cement powder systems constituted an equimolar mixture of tetracalcium phosphate (Ca₄(PO₄)₂O) and dicalcium phosphate dihydrate (CaHPO₄2H₂O), hydroxyapatite (HAP, Ca₁₀(PO₄)₆(OH)₂) seed crystals and sodium bicarbonate. Two types of 2% IMC loaded-cements were prepared as follows, one containing 0% HAP seed crystal and 0–10% sodium bicarbonate, and the other containing 40% HAP seed crystal and 0–10% sodium bicarbonate. The drug release profiles from 2% IMC loaded-cements were measured in simulated body fluid at pH 7.25 and 37.0°C. Results. The drug release profiles from the cement matrix systems with or without seed crystals were estimated using a moment analysis computer program. The mean drug release time (MDT) and the time required for 50% drug release of the cement containing 0 and 40% seed crystal decreased with an increase of sodium bicarbonate. Furthermore, after the drug release the total pore volume of the cement matrix, as measured by mercury porosimetry, increased with an increase of sodium bicarbonate. Conclusions. MDT and T₅₀'s were a function of adding the amount of sodium bicarbonate. The results of the relationship between the micropore distribution, total volume of pores after drug release and drug release supported the hypothesis that the variation in drug release from the cements resulting from the addition of sodium bicarbonate was mainly due to an increase in the diffusion of the drug in the micropores of the cement by dissolution or erosion of the cement matrix.     

Bilayer Composition,Temperature, Speciation Effects and the Role of Bilayer Chain Ordering on Partitioning of Dexamethasone and its 21-Phosphate

Purpose

Models to predict membrane-water partition coefficients (K_p) as a function of drug structure, membrane composition, and solution properties would be useful. This study explores the partitioning of dexamethasone (Dex) and its ionizable 21-phosphate (Dex-P) in liposomes varying in acyl chain length, physical state, and pH.

Methods

DMPC:mPEG DMPE, DPPC:mPEG DPPE, and DSPC:mPEG DSPE (95:5 mol%) liposomes were prepared by thin film hydration. K_p values for Dex and Dex-P were determined from pH 1.5–8 by equilibrium dialysis and equilibrium solubility (Dex).

Results

Dex K_p values at 25°C were 705?±?24, 106?±?11, and 58?±?9 in DMPC, DPPC, and DSPC, increasing to 478?±?20 in DPPC liposomes at 45°C. Both neutral and anionic species contributed to the K_p of Dex-P versus solution pH (1.5–8). A linear correlation was found between the natural logarithm of K_p and the inverse of bilayer free surface area (1/a_free) where a_free is a parameter reflecting chain ordering that depends on bilayer composition and temperature.

Conclusions

Models of the pH dependence of partitioning of ionizable compounds must include contributions of both neutral and ionized species. Bilayer free surface area may be an important variable to predict K_p of drug molecules versus lipid composition and temperature.

     

Complexation of Nifedipine with Substituted Phenolic Ligands

The bioavailability of nifedipine in man is highly variable. This may be partly due to its poor aqueous solubility (5–6 µg/ml over pH 2.2–10.0, as determined in this laboratory). We initiated this study to examine the enhancement of aqueous nifedipine solubility via complexation. A series of substituted aromatic ligands was studied to identify those structural features important for complexation with nifedipine. The studies were performed at 25°C employing the solubility technique, using pH 2.2 or 7.0 buffers at an ionic strength of 0.25 M. The apparent equilibrium complexation constants for the 1:1 and/or 1:2 complexes were determined, where appropriate. A linear free-energy approach was used to relate K _1:1 with Hammett's sigma () and fractional partition coefficient () parameters. The following correlation was obtained: log (K _l:l/K _o = 0.31 + 0.l0 + 0.36 (r ² = 0.86, P < 0.003, N = 9), where K _o is the complexation constant for phenol. Statistical analyses showed that was more important than in affecting nifedipine complexation. The exact location of this interaction on the nifedipine molecule is undefined at present.     

阿齐沙坦油水分配系数的测定

目的 测定阿齐沙坦的油水分配系数。方法 配制不同pH值的磷酸盐缓冲液,以正辛醇-磷酸盐缓冲液作为分散系统,摇瓶法作为测定方法,照紫外-可见分光光度法（《中国药典》2010年版附录ⅣA）进行测定。通过阿齐沙坦分配平衡后在油相（正辛醇）和水相的浓度比,计算油水分配系数。结果 在正辛醇-磷酸盐缓冲液体系中,pH＝3.0时阿齐沙坦的油水分配系数为3.78,pH＝7.0时阿齐沙坦的油水分配系数为?0.30。结论 应用摇瓶-紫外分光光度法,能够准确测定阿齐沙坦的油水分配系数,并由此推测其体内过程。     

Amino Acid Side-Chain Contributions to Free Energy of Transfer of Tripeptides from Water to Octanol

The location of amino acids in soluble or membrane proteins is related to the hydrophobicity of the side chains. Amino acid hydrophobicity values are based upon the thermodynamics of transfer from an aqueous to a nonaqueous environment. However, for certain hydrophilic residues uncertainty exists on the appropriate hydrophobicity values. We have measured the octanol- water partition coefficients (P _o/w) of tripeptides of the sequence N-14-C-acetyl-Ala-JT-Ala-NH-tButyl (AcAlaXAlaNHtButyl), where the central residue X was either Gly , Ala, Phe, Trp, Pro, His, Asp, or Glu. The P _o/w for the tripeptides agreed reasonably well with values calculated by the fragment method of D. J. Abraham and A. J. Leo (Proteins Struct. Func. Gen. 2, 130–152, 1987). The log P _o/w of the uncharged form was 1.6,2.7, and 2.5 greater than the log P _o/w of the ionized form for the His, Asp, and Glu peptide, respectively. The new data on the pH dependence of the ionizable side chains, His, Asp, and Glu, should result in better prediction of the partition coefficient of peptides as a function of pH. The thermodynamic parameters were determined from the temperature dependence of partitioning. In the temperature range studied (2 to 65°C) the transfer of tripeptides from water to octanol was entropy governed except for the ionized peptides. A heat capacity term was necessary to account for the transfer of tripeptides containing non polar residues. The heat capacity change for transfer from water into octanol was –45, –73, –81, and –88 cal/mol K for Ala, Phe, Trp, and Pro peptides, respectively. Peptides containing Gly, His (pH 7.2), and the uncharged forms of Asp, Glu, and His did not show a significant change in heat capacity. The side-chain contribution of the central residue X (G _X) to the free energy of transfer was obtained from the difference between the free energy o f transfer of the peptide containing the central residue X and the Gly peptide; G _X = G _{(AcAlaGlyAlaNHtButyl)} - G _{(AcAlaGlyAlaNHtButyl)}. The relative order of hydrophobicity of the side chains correlated well with previous studies. However, a significant difference was found for the absolute hydrophobicity between the present study and experimental data on N-acetyl amino acid amide derivatives (J. Fauchere and V. Pliska, Eur. J. Med. Chem. 18(4), 369–375, 1983). The G _X values at pH 7.2 were 0, –0.13, –2.19, –2.52,–0.29, –0.16, 3.50, and 3.12 kcal/mol for Gly, Ala, Phe, Trp, Pro, His, Asp, and Glu, respectively. These hydrophobicity values in a tripeptide environment provide suggested values for a hydrophobicity scale.     

Rapid Determination of Oral Pharmacokinetics and Plasma Free Fraction Using Cocktail Approaches: Methods and Application

Purpose. To apply cocktail approaches for protein binding (PB) and pharmacokinetics (PK) within a discovery program as a means of providing timely systemic exposure (AUC and C_max) data. Methods. For PB data, a procedure of cocktail ultrafiltration, mixed matrix sample preparation and single quadrupole atmospheric pressure ionization LC/MS analysis was used. In vivo PK studies consisted of 4 experimental compounds and a control compound dosed orally at 1 mg/kg (5 mg/kg total dose), with plasma samples obtained at 0.5, 1, 2, 4 and 8 h post dose. For PB and in vivo PK analysis, a control compound was tested within each cocktail to ensure consistent reproducibility. Results. Approximately 2 weeks were spent comparing single and cocktail approaches to determine the feasibility of this method for this project. Comparisons of cocktail data with single compound data revealed no significant differences between the approaches. The oral AUC values ranged from 0.01 to 9.28 ghr/ml and the C_max values ranged from 0.04 to 2.17 g/ml. Free fractions of the 44 compounds studied ranged from 0.006 to 0.271. Using the free fraction values to correct for free AUC and C_max results in ranges of 0.001 to 0.473 ghr/ml, and 0.001 to 0.119 g/ml, respectively. Conclusions. All 44 compounds tested had similar potencies in vivo. Thus, these results suggest that a respective 400 and 100-fold range in AUC and C_max corrected for free fraction exist in the presence of comparable in vivo activity. The ability to generate this type of data in a timely manner allowed the selection of a candidate with low peripheral exposure relative to the effective dose. The free fraction and PK data on the 44 compounds described was collected within three work days by 2 lab scientists.     

氢溴酸沃替西汀油水分配系数研究及其片剂的一致性评价

目的 测定氢溴酸沃替西汀油水分配系数并对其片剂进行一致性评价。方法 模拟体内环境配制不同pH的缓冲液(或水溶液),以正辛醇-缓冲液(或水溶液)为分散系统,摇瓶法作为测定方法,采用高效液相色谱法进行测定。通过氢溴酸沃替西汀分配平衡后在油相(正辛醇)和水相的浓度比,计算氢溴酸沃替西汀的油水分配系数,并对比测定氢溴酸沃替西汀片剂(自制片、原研片)中氢溴酸沃替西汀的油水分配系数。结果 在正辛醇-缓冲液(或水溶液)体系中,pH=1.0时氢溴酸沃替西汀的油水分配系数为2.20;pH=4.5时为2.18;pH=6.8时为0.823;在水中时为0.657。结论 采用摇瓶-高效液相色谱法能够准确测定氢溴酸沃替西汀的油水分配系数,为预测体内吸收过程提供依据。并且氢溴酸沃替西汀自制片和原研片中氢溴酸沃替西汀油水分配系数结果一致。     

In Vitro and In Situ Permeability of a 'Second Generation' Hydroxypyridinone Oral Iron Chelator: Correlation with Physico-Chemical Properties and Oral Activity

Purpose. The in vitro and in situ transport of CGP 65015 ((+)-3-hydroxy-1-(2-hydroxyethyl) -2-hydroxyphenyl-methyl-1 H-pyridin-4-one), a novel oral iron chelator, is described. The predictive power of these data in assessing intestinal absorption in man is described. Methods. Caco-2 epithelial monolayer and in situ rat jejunum perfusion intestinal permeability models were utilized. In vivo iron excretion and preliminary animal pharmacokinetic experiments were described, lonization constants and octanol/aqueous partition coefficients were measured potentiometrically. Solubilities and intrinsic dissolution rates were determined using standard procedures. Results. Caco-2 cell (P_app 0.25 X 10^–6 cm.s^–1) and rat jejunum (P_w 0.4) permeabilities of CGP 65015 were determined. The log D(pH 7.4) of CGP 65015 was 0.58 and its aqueous solubility was > 0.5 mg.ml^–1 (pH 3–9). The intrinsic dissolution rate of CGP 65015 in USP simulated intestinal fluid was 0.012 mg.min^–1.cm^–2. CGP 65015 promotes iron excretion effectively and dose dependently in animals. Conclusions. Caco-2 and rat intestinal permeabilities predict incomplete oral absorption of CGP 65015 in man. Preliminary rat pharmacokinetics support this. Physico-chemical data are, also, in line and suggest that CGP 65015 may, in addition, be solubility/dissolution rate limited in vivo. Nevertheless, early animal pharmacological data demonstrate that CGP 65015 is a viable oral iron chelator candidate.     

Controlled Release Gel of Ibuprofen and Lidocaine in Epidural Use—Analgesia and Systemic Absorption in Pigs

Purpose. Reduction of the frequency of injections and localization of the absorption of drug molecules to the injection site would be of great advantage in epidural pain treatment. The epidural use of a controlled release gel of lidocaine and ibuprofen was studied. Methods. The effect of a poloxamer gel (25%) containing 2% lidocaine HC1 and 2% ibuprofen Na on the duration of analgesia after epidural administration to pigs was compared with drug in solution. Analgesia was assessed by observing the motor function and the nociceptive reflex-withdrawal response to painful pressure stimulation on the feet. Pharmacokinetic and histological examinations were performed. Results. Analgesia lasted significantly longer after epidural lidocaine gel injection in comparison with the solution. The gel prolonged the systemic absorption, thereby increasing the epidural availability of lidocaine for spinal analgesia. Although the absorption of ibuprofen was prolonged after epidural gel injection, the duration of analgesia as compared with the solution was not prolonged. After epidural injection, only slight inflammatory changes were observed in the tissue structures of the epidural space, but none in the spinal cord. Conclusions. These results demonstrate poloxamer gel to be a promising controlled-release, injectable epidural formulation for the management of pain.     

Estimation of Octanol-Water Partition Coefficients and Correlation with Dermal Absorption for Several Polyhalogenated Aromatic Hydrocarbons

n-Octanol-Water partition coefficients (K_ow)were experimentallyestimated for: 2,3,7,8-tetrachloro- and 2,3,7,8-tetrabromodibenzo-p-dioxin;2,3,7,8-tetrachloro-, 2,3,7,8-tetrabromo-, and 1,2,7,8- tetrabromodibenzofuran;1,2,3,7,8- pentachioro-, 1,2,3,7,8-pentabromo-, 2,3,4,7,8-pentachloro-,and 2,3,4,7,8- pentabromodibenzofuran; 1,2,4,6,8,9-hexachlorodibenzofuran(HxCDF), and 3,4,3',4'-tetrachlorobiphenyl (3,4,3',4'-TCB).The method involved correlation of literature K_ow with reversephasehigh-performance liquid chromotography (RP-HPLC) retention timefor a series of 23 calibration standards and estimation of K_owfor test compounds from measured RP-HPLC retention. Retentiontimes for all standards and test chemicals were measured induplicate on the same octadecasilane (C₁₈ reverse-phase columnwith an isocratic 85:15 methanol:water mobile phase; soluteswere detected by uv absorbance (254 nm). Literature log K_owvalues used for the calibration standards had been measuredexclusively by the generator column method. Log K_ow estimatesfor the test compounds in the present study ranged from 5.45for 3,4,3',4'-TCB to 6.81 for HxCDF. K_ow estimates were thenplotted against laboratory data for the in vivo 3-day dermalabsorption of single equimolar doses (200 pmol and 20 nmol,or 1 nmol/kg and 0.1 µmol/kg) of selected test compoundsin male F344 rats. Strong inverse correlations were found betweenoctanol-water partition coefficient estimates and single-dosedermal absorption for most of the compounds studied. In addition,RP-HPLC retention time itself appeared to be as equally suitedas K_ow to such correlations with dermal absorption. The structure-activityrelationships suggested in this study were sought in order toexplain observed differences in the dermal absorption of polyhalogenateddibenzo-p-dioxin, dibenzofuran, and biphenyl congeners differingin number, position, and/or type (Cl or Br) of halogen substituents.Moreover, these results should be of predictive value in therisk assessment of dermal exposure to polychlorinated dibenzo-p-dioxins,dibenzofurans, biphenyls, and their brominated analogues.     

Predicting Skin Permeability

Published permeability coefficient (K _p) data for the transport of a large group of compounds through mammalian epidermis were analyzed by a simple model based upon permeant size [molecular volume (MV) or molecular weight (MW)] and octanol/water partition coefficient (K _oct). The analysis presented is a facile means to predict the percutaneous flux of pharmacological and toxic compounds solely on the basis of their physicochemical properties. Furthermore, the derived parameters of the model have assignable biophysical significance, and they provide insight into the mechanism of molecular transport through the stratum corneum (SC). For the very diverse group of chemicals considered, the results demonstrate that SC intercellular lipid properties alone are sufficient to account for the dependence of K _p upon MV (or MW) and K _oct. It is found that the existence of an aqueous-polar (pore) pathway across the SC is not necessary to explain the K _p values of small, polar nonelectrolytes. Rather, their small size, and consequently high diffusivity, accounts for their apparently larger-than-expected K _p. Finally, despite the size and breadth of the data set (more than 90 compounds with MW ranging from 18 to >750, and log K _oct ranging from –3 to + 6), the postulated upper limiting value of K _p for permeants of very high lipophilicity cannot be determined. However, the analysis is able to define the physicochemical characteristics of molecules which should exhibit these maximal K _p values. Overall, then, we present a facile interpretation of a considerable body of skin permeability measurements that (a) very adequately describes the dependence of K _p upon permeant size and lipophilicity, (b) generates parameters of considerable physicochemical and mechanistic relevance, and (c) implies that the SC lipids alone can fully characterize the barrier properties of mammalian skin.     

The Stability and Solubility of Progabide and Its Related Metabolic Derivatives

The stability–pH profile of the -aminobutyric acid prodrug, Progabide, was found to be bell shaped, with maximum stability occurring at pH 6 to 7 with a t _1/2 of 126 min. Of its metabolic derivatives, the deamidated product PGA degraded in a similar fashion to Progabide, whereas the hydrolytic degradation product SL79.182 was, as expected, a stable compound. Progabide behaved as a typical weak base, with its solubility increasing with a decrease in pH. SL79.182 behaved as a typical phenolic weak acid, with its solubility increasing with an increase in pH. Both compounds displayed low intrinsic solubilities of 14.5 × 10^–5 M for Progabide and 33.4 × 10^–6 M for SL79.182. An increase in temperature resulted in an increase in the solubility but a decrease in the stability of Progabide. The data obtained indicate that the gastric pH and gastric emptying rate will have a profound effect on the oral bioavailability of Progabide.     

Crystalline to Amorphous Transition of Disodium Hydrogen Phosphate During Primary Drying

Purpose. To monitor the phase transitions during freeze-drying of disodium hydrogen phosphate. Methods. The variable temperature sample stage of the X-ray diffractometer (XRD) was attached to a vacuum pump, which enabled the entire freeze-drying process to be carried out in the sample chamber. The phase transitions during the freeze-drying cycle were monitored in real time by XRD. Aqueous buffer solution (containing disodium hydrogen phosphate and sodium dihydrogen phosphate) was cooled at 2°C/min from room temperature to –70°C. It was then heated to –25°C and subjected to primary drying for 2 h at a chamber pressure of 100 mTorr, followed by secondary drying at –10°C. Results. In the frozen solution, disodium hydrogen phosphate had crystallized as the dodecahydrate (Na₂HPO₄12H₂O) as was evident from its characteristic lines at 5.37, 4.27, and 2.81 Å. Primary drying for 2 h resulted in ice sublimation, and the complete disappearance of the dodecahydrate peaks. Conclusion. The dehydration of the crystalline dodecahydrate resulted in an amorphous anhydrate. Thus the amorphous nature of the end product is a result of phase transitions during the process and do not reflect the solid-state of the ingredients during the entire process.