This dissertation discusses some aspects of the solubilization of drugs from the perspective of the formulator. Chapter I emphasizes the importance of this research as well as the study of the practical aspects of aqueous solubilization of drugs. The most important solubilization techniques such as pH control, cosolvency, micellization, and complexation are introduced in Chapter II. Chapter III evaluates specifically the cosolvency technique by means of a discussion of the effect of pharmaceutically acceptable cosolvents upon the solubilization of several drugs. Chapter IV discusses the micellization technique in detail. In this chapter, the effect of Tween 80 on the solubilization of several drugs is evaluated. Finally, in Chapter V, the consequences of the dilution of a pH solubilized formulation are evaluated by means of two in vitro formulation dilution methods.

The National Library of Medicine Classification Scheme (NLMC) was developed in 1946 utilizing basic ideas from Eileen Cunningham's Medical Library Classification, a classification scheme developed from the viewpoint of teaching medicine. Three classification schemes have been developed for the organization of pharmaceutical literature: (1) Eli Lilly Company, (2) Sheppard Library at the Massachusetts College of Pharmacy, and (3) Lloyd Library, University of Cincinnati. There is no evidence in the literature that these classification schemes are kept up-to-date. Since the NLMC is the only up-to-date classification scheme available in the United States for the organization of health sciences literature, it would be an important contribution to determine how adequate the system is for organizing health sciences literature other than medicine. The purpose of this study was to examine how the structure of the NLMC accommodates pharmaceutical literature, to determine its adequacy in organizing this body of literature, and to contribute seminal knowledge on the history and development of this classification scheme. / The basic tools used in the study were a list of disciplines of the pharmacy field published by the American Association of Colleges of Pharmacy (AACP), the NLMC, the Medical Subject Headings (MeSH), six bibliographies representing the recommended resources necessary to support the pharmacy discipline, and CATLINE. The six bibliographies were merged using the computer program Pro-Cite to generate a database named Asklepios. The study was limited to an analysis of the NLMC classification numbers assigned to bibliographic records of monographs representing the body of literature on pharmacy. The study population was 1,979 records. In the NLMC pharmacy literature is accommodated in subclass QV 701-835 Pharmacy and pharmaceutics. The research revealed five fundamental categories provided in the NLMC for pharmacy literature. Ten fundamental categories were identified in the published pharmacy literature. The analysis revealed that the structure of the NLMC brought together 42 percent of the literature, 41 percent was scattered throughout the classification scheme, and 17 percent was classified in the Library of Congress Classification. / Source: Dissertation Abstracts International, Volume: 55-09, Section: A, page: 2618. / Major Professor: Doris H. Clack. / Thesis (Ph.D.)--The Florida State University, 1994.

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Aqueous solubility is one of the most important physical properties to consider in drug discovery and development. Drug candidates with poor solubility often have poor bioavailability, which leads to increased developmental cost and efforts. Therefore, there is a strong trend to perform solubility screening of drug candidates as early as possible in the drug discovery and development process. While experimental methods are being developed to increase the throughput of solubility measurement, the development of aqueous solubility prediction methods can be a powerful complementary tool. This dissertation starts by compiling a large collection of aqueous solubility data for organic compounds covering diverse classes of structures. The data set is first used to critically evaluate the General Solubility Equation (Yalkowsky et al., 1980, 1999), one of the most widely used methods for aqueous solubility prediction. The General Solubility Equation performs very well overall as measured by the average absolute error (AAE) of 0.56 log unit. Detailed analyses indicate that it gives better predictions for non-electrolytes than some classes of weak electrolytes. This method is then compared with a method based on an amended solvation energy relationship, which considers the hydrogen bonding potentials of functional groups. It is shown that averaging the prediction results from the two methods gives better prediction than either method alone. Following the concept of the AQUAFAC model developed by Myrdal et al. (1992, 1993, 1995), an extended version of the original structural fragmentation scheme is developed. The model is trained on the data set and has an R2 value of 0.881 and a standard error of estimation of 0.819 log unit. Group contribution parameters for a set of 104 fragments are obtained. A new group contribution model is developed to suit the needs in the early drug discovery stage, when melting information is generally not available. Calculated octanol-water partition coefficient is included in the model. The model has a standard error of estimation of 0.814 log unit. When evaluated on independent test sets, the new model provides comparable prediction results with the other two models. The independence of the new model of experimental melting information makes it a suitable tool for aqueous solubility screening in early drug discovery.

SarCNU (NSC364432, 1-(2-chloroethyl)-3-sarcosinamide-1-nitrosourea), is a new antitumor agent of the nitrosourea family. Solubilization studies have shown that SarCNU is soluble in a variety of solvents including water. However, it is highly unstable in aqueous solutions with its t90 of 6 hrs in water. Therefore, the overall purpose of this project is to investigate the stabilization of this drug in various conditions. Two parental formulations are also proposed based on the result of stabilization study. The stability of SarCNU at different pH, temperature, and pharmaceutically acceptable solvents were investigated by HPLC. The influences of light, pH (2.0, 4.0, 6.0, and 8.5) at 0.01M and 0.1M phosphate buffer, antioxidants (ascorbic acid and sodium bisulfite), and a chelating agent (disodium EDTA) at pH 2.0 and pH 6.0 were studied at room temperature. The stability of the drug was also determined in water, pharmaceutically acceptable solvents, and in different combinations of these solvents at 4 different temperatures (25, 37, 50, and 60°C). The degradation of the drug, which was catalyzed not only by specific acid and base, but also by general acid and base, follows first order kinetics. Antioxidants, EDTA, and light have no effect on the degradation rate, suggesting oxidation is not the main degradation pathway. The t90 in pure cosolvent was twenty-five to fifty times higher than that in water or semi-aqueous vehicles. One major degradation product was confirmed by GC-MS and NMR. Two other possible degradation products were also suggested by GC-MS. The degradation products suggest that the degradation of SarCNU involves hydrolysis of its amide group. The stability profile suggests that we can increase the shelf life of the drug by the use of a pure cosolvent. This approach can be used to store drug so that it can be diluted with aqueous solvent prior to injection with the aid of a double syringe. A freeze-dried formulation is also studied. Neat tertiary butyl alcohol (TBA), a low toxicity, high vapor pressure and low melting solvent, was determined to be an excellent medium for SarCNU. Lyophilization of SarCNU from pure TBA produces a uniform cake composed of needle-shaped crystals. Thermal analysis and gas chromatography indicate that the cake contains less than 0.001% residual solvent. The SarCNU cake can be readily reconstituted with either water or an aqueous solution of 40% propylene glycol and 10% ethanol. These reconstituted solutions are stable for 4 and 13 hours, respectively.

The primary objectives of this research were to (1) estimate survival functions and the natural history of patients infected with human immunodeficiency virus who are using antiretroviral medication with a protease inhibitor and those who are under treatment protocols without protease inhibitors, and (2) estimate average lifetime treatment costs of infected patients for both drug regimens. A secondary objective was to provide a step by step discussion of the applicability of a Markov process in modeling survival and cost profiles of acquired immunodeficiency syndrome, a complex set of diseases, to managed care organizations. Data used in this study were collected using two techniques: expert physician panel interviews and a literature search. The transition rates for patients moving from one disease state to another were obtained from both sources. Cost estimates were calculated predominantly from published literature. The fundamental matrix solution of a Markov chain model was used to estimate survival functions, natural history profiles, and lifetime costs of therapy for HIV-infected patients. The research was conducted from the perspective of a managed health care organization. Results indicated that protease inhibitors significantly improved overall survival of infected patients by deterring the progression of disease and onset of various opportunistic infections. Lifetime costs of treatment, however, were substantially higher for treatment protocols using protease inhibitors as one of the components of recommended combination retroviral therapy. Estimates obtained from this study also indicated that unless significant reductions in high resource intensive events such as hospitalization can be achieved, protease inhibitors might not be cost efficient in treating HIV-infected patients. Lastly, this research showed that Markov modeling techniques can offer valuable benchmarks for both clinical and economic decision making in planning disease intervention to improve health outcomes and evaluate costs.

4-Dedimethylamino sancycline (col-3) is a new antitumor antibiotic of the tetracycline family. Preformulation studies have indicated that col-3 is not stable in aqueous solutions. The overall purpose of this research project is to investigate the stability kinetics of this drug in aqueous solutions. The physicochemical properties of col-3, including melting point, UV spectrum, mass spectrum, dissociation constants and solubility were determined. Col-3 is an acidic compound with two pKₐ values of 5.9 (pKₐ₁) and 8.1 (pKₐ₂). It is slightly soluble in water (0.01 mg/mL) and readily soluble in organic solvents such as polyethylene glycol and benzyl alcohol. Although the solubility of col-3 increases with increasing pH, its stability decreases with increasing pH. A HPLC assay was developed to quantitate col-3 and separate its degradation products. Four major degradation products of col-3 were detected under alkaline conditions. These degradates were identified by their elution times and their UV-absorption spectra. The kinetics of degradation of col-3 in aqueous solution at 25°C were investigated by HPLC over the pH-range of 2-10. The Influence of pH, buffer concentration, light, temperature and some additives on the degradation rate were studied. The degradation of col-3 was found to follow first-order kinetics at 25°C. A rate expression covering the degradation of the various ionic forms of the drug was derived and shown to account for the shape of the experimental pH-rate profile. Under basic conditions, the degradation of col-3 involves oxidation, which is catalyzed by metal ions. The separation of the four initial degradation products of col-3 was investigated. Partial separation of these compounds is achieved by liquid-liquid extraction. However, due to the instability of these compounds, their complete isolation cannot be successful. The UV spectroscopic analysis of these compounds shows that an absorbance at 360 nm is partially decreased in degradates I and II and totally absent in degradates III and IV. These results suggest that the phenolic diketone moiety, which produces this absorption band, has been altered upon degradation.

Drugs often require formulation techniques to increase their solubility and/or increase their stability in aqueous media. In cases where solubility enhancement is necessary, ideally, the physical stability of the formulation should be maintained upon administration. Unfortunately, in some cases, drugs precipitate out of solution when the formulation is introduced into aqueous media. Intravenously, drug precipitation can cause phlebitis and orally, it can hinder absorption. In order to avoid phlebitis, new intravenous (IV) parenterals are commonly screened by injection into animals. An in vitro dynamic injection model is introduced and validated. Twenty-one currently marketed IV products were used to investigate the validity of the model. Logistic regression and a receiver operator curve (ROC) indicate a value of 0.003 to best delineate phlebitic and non-phlebitic products. Measures of sensitivity (0.83), specificity (0.93), positive predictive value (0.93) and negative predictive value (0.78) indicate the model's accuracy and reliability. The model was tested to screen different formulations of a new proprietary antibiotic, Van-An. The opacities obtained for the formulation with acetate addition were significantly smaller than for the phosphate buffered formulation at 4 injection rates. In general the results suggest acetate as a better buffer species than phosphate for the pH range defined. The solubilization and stabilization of an orally administered formulation of a new anti-hepatitis C drug, PG301029, is established through a novel method of complexation. Hydroxypropyl-beta-cyclodextrin (HPbetaCD) and PG301029 are dissolved in glacial acetic acid. The acetic acid is removed by roto-evaporation such that the drug exists primarily in the complexed form. Formulated PG301029 is found to be stable upon storage and, once reconstituted, the powder dissolves rapidly and PG301029 remains stable for 21 hours. Acetic acid and HPbetaCD provide several formulation advantages. PG301029 and HPbetaCD are both soluble in acetic acid. Once prepared, the formulation can be stored in solid form. Upon reconstitution, the cyclodextrin both protects the drug from water and enhances the solubility of PG301029. This unique method results in a solid dosage form of PG301029 which is soluble, stable and highly bioavailable in mice when given orally.

The bioassay guided fractionation of two Latin American plants, structure elucidation of pure isolates, and LC/MS studies of six plant extracts is presented here along with the structure determination of two compounds using X-ray diffraction. The bioassay guided fractionation of the antibacterial and antitubercular CH2Cl2-MeOH extracts of the Argentinean plant Caiophora coronata Hook. et Arn. (Loasaceae) and the Chilean plant Myrcianthes coquimbensis (Barn.) Landrum et Grifo (Myrtaceae) respectively led to the isolation and complete structure elucidation of nine compounds from the active fractions. Three of these isolates were determined to be new. Namely, a new triterpene, 1beta,3beta-dihydroxyurs-12-en-27-oic acid, a new iridoid, 1alpha-methoxy-6alpha,10-dihydroxyisoepiiridomyrmecin (caiophoraenin) from C. coronata and a new monoterpene (1S,3 S,4R)-1-methyl-4-(1-methylethenyl)-1,3-cyclohexanediol from M. coqumibensis. All chemical structures were established unequivocally by physical and spectroscopic techniques including-melting point, optical rotation, 1D and 2D NMR, HR-FABMS, and FT-IR. Absolute configuration of the new monoterpene was established by Mosher's esterification. The antibacterial activity of all isolates from C. coronata were determined against methicillin-sensitive (MSSA) and -resistant (MRSA) strains of Staphylococcus aureus, Bacillus subtilis (BS), vancomycin-resistant Enterococcus faecium (VREF), Escherichia coli (EC), E. coli imp (ECimp), and Candida albicans (CA). 1beta,3beta-Dihydroxyurs-12-en-27-oic acid was found active against BS, MSSA, MRSA, VREF, and ECimp with MIC values of 2, 4, 4, 4 and 16 mug/ml respectively, whereas, other isolates were essentially inactive. The antitubercular activity of all isolates from M. coquimbensis was evaluated against M. tuberculosis using the microplate alamar blue assay. Oleanolic acid was determined to be the active principle of the extract with an MIC value of 29.66 mug/mL whereas other isolates were regarded as inactive (MIC > 128 mug/mL). Chemical investigations by LC/MS of species closely related to C. coronata and M. coquimbensis were also conducted. Structure solutions by single crystal X-ray crystallography, of an iridoid (4R,5R,7S,8S,9 S)-(-)-7-hydroxy-8-hydroxymethyl-4-methylperhydrocyclopenta[ c]pyran-1-one, and a fernane (3R,5S,9 R,10S,13S,14S,17 R,18R,21R)-(-)-fern-7-ene-3alpha-ol, isolated from the antitubercular methanolic extracts of Valeriana laxiflora DC (Valerianaceae) and Sebastiania brasiliensis Spreng. (Euphorbiaceae) respectively is also presented. The absolute configuration of these compounds was also determined.

This dissertation, completed as part of an International Cooperative Biodiversity Group (ICBG) Program, encompasses the field collection, taxonomic determination, bioassay-guided isolation, and chemical characterization of three plants native to Chile, each of which was collected using a distinct collection approach. Chuquiraga ulicina ssp. ulicina , collected by the ecological or environmental strategy, yielded ten compounds including four novel taraxastane-type triterpenoids, 3β-acetoxy-6β-hydroxytaraxasta-20-ene (1), 6β-hydroxytaraxast-20-en-3-one (2), 6β-hydroxytaraxasta-20-ene 3β-palmitate (3), and 3β, 6β-dihydroxytaraxasta-20-ene (4), together with the known triterpenoids lupeol (5), lupenyl acetate (6), lupenone (7), friedelinol ( 8), 3β-acetoxy-30-nor-lupan-20-one (9), and 30-norlupan-3β-ol-20-one (10). Lupeol (5) was the only compound to show antitubercular activity. Sphacele salviae, collected by the ethnobotanical or ethnomedical approach, allowed the isolation of three known compounds, including the two abietane diterpenoids carnosol ( 11) and rosmadial (12), as well as one pentacyclic triterpenoid, ursolic acid (13). Greigia sphacelata, collected according to the random approach, afforded nine compounds. These include the two novel flavanones 5,7,3'-trihydroxy-6,4' ,5'-trimethoxy flavanone (14) and 5,3'-dihydroxy-6,7,4',5 '-tetramethoxy flavanone (15), as well as four known phenylpropanoids, 1,3-O-di-trans-p-coumaroylglycerol (16), 1-O-trans-cournaroylglycerol (17 ), 1-(ω-feruloyldocosanoyl)glycerol and 1-(ω-feruloyltetracosanoyl)glycerol (18), and trans-ferulic acid 22-hydroxy docosanoic acid ester (19), and three known pentacyclic triterpenoids, arborinone (20), arborinol (21), and isoarborinol (22).