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Hydrophilic polymers in a swellable matrix tablet hydrate quickly to form a hydrogel layer on the exterior of the dosage once in contact with water or biologic fluid. The resultant hydrogel serves as a barrier to regulate water permeation into the matrix and drug diffusion from the preparation. It is therefore important to understand how the polymer is hydrated and what mechanism exists between hydrogel formation and drug dissolution from a swellable matrix tablet. In this thesis, a TA texture analyzer was utilized to monitor and characterize matrix swelling properties during dissolution process. Multiple regression models were employed to analyze the quantitative relationship between drug dissolution or hydrogel thickness and major formulation factors (polymer ratio, drug solubility). Modified release matrix tablets were prepared using four APIs with a range of aqueous solubility, i.e., acetaminophen (ACE), chlorpheniramine (CHL), ibuprofen (IBU), and pseudoephedrine hydrochloride (PSE). Two hydrophilic polymers, polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) were selected and tested as primary matrix polymers for the formulations. It was found from the experiments that multiple regression model was capable of estimating drug dissolution for both PEO and HPMC matrix preparations. Based on major formulation factors the regression models provide satisfactory prediction of drug release, which could further aid in formulation development and optimization.

Hydrophilic polymers in a swellable matrix tablet hydrate quickly to form a hydrogel layer on the exterior of the dosage once in contact with water or biologic fluid. The resultant hydrogel serves as a barrier to regulate water permeation into the matrix and drug diffusion from the preparation. It is therefore important to understand how the polymer is hydrated and what mechanism exists between hydrogel formation and drug dissolution from a swellable matrix tablet. In this thesis, a TA texture analyzer was utilized to monitor and characterize matrix swelling properties during dissolution process. Multiple regression models were employed to analyze the quantitative relationship between drug dissolution or hydrogel thickness and major formulation factors (polymer ratio, drug solubility). Modified release matrix tablets were prepared using four APIs with a range of aqueous solubility, i.e., acetaminophen (ACE), chlorpheniramine (CHL), ibuprofen (IBU), and pseudoephedrine hydrochloride (PSE). Two hydrophilic polymers, polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) were selected and tested as primary matrix polymers for the formulations. It was found from the experiments that multiple regression model was capable of estimating drug dissolution for both PEO and HPMC matrix preparations. Based on major formulation factors the regression models provide satisfactory prediction of drug release, which could further aid in formulation development and optimization.

The physicochemical properties of a drug affect to a large extent its subsequent biological absorption and bioavailability profile. Considerable pharmaceutical interest is therefore directed torwards the improvement of drug dissolution characteristics of drugs with low aqueous solubility. This thesis has considered the controlled modification of drug dissolution profiles by means of incorporating low concentrations of hydrophilic polymers by different processes into a host drug substance. In order to examine this approach and its potential use, the physicochemical, solid state, stability and tableting properties of a poorly aqueous soluble drug, phenylbutazone, in alternative polymorphic form and containing low levels of two hydrophilic polymers - hydroxypropyl methylcellulose (H.P.M.C.) and the surfactant poloxamer 188 - prepared by both conventional crystallisation and spray drying are reported. As an integral nart of the work attempts were mado to identify the different polymorphic forms of phenylbutazone. The δ-form, the commercially available stable form and the α and β metastable forms (nomenclature after Muller, 1978) were isolated. The α form was found to be unstable on storage. A 2 fold increase in intrinsic dissolution rate was observed for the metastable β-polymorph compared with the stable δ-polymorphic form. The effect of crystallisation rate on the formation of polymorphs of phenylbutazone was studied using a mini-spray dryer, and slower rates of crystallisation were found to favour polymorph formation. The hydrophilic polymers, H.P.M.C. and poloxamer 188, were incorporated by conventional crystallisation and spray drying into the drug crystal. Samples were subjected to a series of tests including differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, and intrinsic dissolution and solubility. When prepared by conventional crystallisation H.P.M.C. was found to form a "high energy" complex with phenylbutazone which melted 10°C lower than the parent drug. When prepared by spray drying H.P.M.C. inhibited the formation of the metastable β-polymorph of phenylbutazone. A 2 fold increase in intrinsic dissolution rate was observed for crystallised and spray dried samples containing 2% w/w or more added polymer. Poloxamer 188 did not form a complex with phenylbutazone and unlike H.P.M.C. did not inhibit the formation of the β-polymorph. For both crystallised and spray dried samples a 3 fold increase in dissolution rate was obtained at polymer levels of 1% w/w or above. The increase in dissolution has been attributed to facilitated wetting by lowering of interfacial tension rather than through the formation of micelles. The stability of selected phenylbutazone:polymer samples was tested at elevated temperatures. The stability was found to be affected both by the method of sample preparation and the type of additive. Large breakdowns occurring by a hydrolytic effect were identified for the crystallised phenylbutazone samples containing poloxamer 188. The effects on compaction of phenylbutazone in alternative form and presence of polymeric additives were studied by compressing samples of similar particle sizes of phenylbutazone as supplied (δ-form), samples of spray dried phenylbutazone (β-form) and samples containing different concentrations of H.P.M.C. prepared both by conventional crystallisation and spray drying. Compaction data were analysed according to the Heckel relationship and by force transmission ratio as well as from the tensile strengths of prepared tablets. The presence of H.P.M.C. up to 5% w/w concentration in phenylbutazone did not change the mean yield pressure for the crystallised or spray dried samples, although a difference in mean value was observed between the crystallised and spray dried materials, 93.22 MPa and 147.02 MPa respectively. Force transmission was found to be improved for samples containing H.P.M.C. prepared by both techniques and in general, the tablet tensile strengths for crystallised samples containing H.P.M.C. were approximately three times greater than for spray dried samples at equivalent tablet porosity. Differences are attributed to variation in solid state and particulate properties between samples.

Thesis (Ph.D)--University of Tulsa, 1987. / Bibliography: leaves 99-104.

Magister Pharmaceuticae - MPharm / Background: Zidovudine (AZT) is a very useful drug for the management of Human Immunodeficiency Virus (HIV) infection. Its optimal use is limited by its bitter taste, sparing solubility (20.1 mg/ml) and acid lability. Cyclodextrins (CD) are a class of compounds which can be used to form inclusion complexes with drugs such as AZT to improve it is taste, solubility and palatability. Purpose: This study complexed hydroxypropyl-beta-cyclodextrin (HPβCD) with AZT. The formulated inclusion complex was evaluated for suitability as a dosage form and as a tool for improving AZT’s palatability, solubility and acid liability. Method: AZT was complexed with HPβCD using the lyophilisation method. The binding constant for the formulation was determined by the phase solubility method, and complex formation between AZT and HPβCD evaluated using proton nuclear magnetic resonance (1H NMR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and hot stage microscopy (HSM). Tablets of the inclusion complex were formulated by direct compression, using the least possible amount of excipients, and the dosage form evaluated for hardness, friability, durability, disintegration time and dissolution. Results: The binding constant of the formulation was 3.919, and the degree of incorporation was 4.0 mg AZT/g of CD per complex. 1H NMR showed significant chemical shifts between the inclusion complex and AZT. DSC and TGA analyses showed significant differences in the curves for the pure AZT and HPβCD. Values for tablet hardness, friability, durability and disintegration time were 236 ± 20 N, 0.7 %, 1.02 % and 10.25 minutes, respectively. The solubility of the formulation was 148.08 mg/ml, and its dissolution profile was different from that of the branded formulation. Conclusions: AZT-HPβCD inclusion complex, with a 7.4-fold increase in AZT solubility, was successfully prepared using the lyophilisation method. The binding constant and friability of the formulation were within acceptable limits. Although the hardness value is high, the tablet still disintegrated within acceptable specified times. This study has significant implications for anti-retroviral complex formulations.

En la industria citrícola, las pérdidas económicas más importantes en poscosecha se deben las podredumbres verde y azul, causadas por los hongos Penicillium digitatum (Pers.:Fr.) Sacc. y Penicillium italicum Wehmer. Durante muchos años, se utilizaron ampliamente los fungicidas químicos para el control de estas enfermedades. Sin embargo, la preocupación de los consumidores por el uso excesivo y prolongado de estos productos para el control de las podredumbres ha orientado a los investigadores a buscar métodos alternativos no contaminantes que no depositen residuos peligrosos ni contaminen el ambiente. El uso de películas y recubrimientos comestibles es un método respetuoso con el ambiente que incrementa la vida útil de muchos alimentos incluidas las frutas y verduras. Sin embargo, muy poca investigación se ha enfocado al desarrollo de recubrimientos comestibles compuestos con la adición de compuestos antifúngicos como un nuevo método para controlar las enfermedades poscosecha en frutos cítricos frescos. El objetivo general de esta tesis doctoral fue desarrollar nuevos recubrimientos comestibles compuestos con la adición de aditivos alimentarios antifúngicos para el control de las podredumbres verde y azul en cultivares de cítricos comercialmente importantes. Primero, se desarrollaron las nuevas películas comestibles compuestas en base a hidroxipropil metilcelulosa (HPMC)-lípido con la adición de aditivos alimentarios o compuestos generalmente reconocidos como seguros (GRAS, por sus siglas en inglés), y se seleccionaron de acuerdo a su capacidad de formar emulsiones estables. Las películas se evaluaron por su actividad in vitro contra P. digitatum y P. italicum y sus propiedades mecánicas y de barrera (Capítulo 1). Luego, las emulsiones seleccionadas se usaron para pruebas in vivo en especies y cultivares de cítricos comercialmente importantes y se determinó su actividad antifúngica curativa (fruta recubierta después de la inoculación) y preventiva (fruta recubierta antes de la inoculación fungíca) contra las podredumbres verde y azul (Capítulo 2). / Valencia Chamorro, SA. (2009). Desarrollo de recubrimientos comestibles con actividad antifúngica en frutos cítricos [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/6286 / Palancia

The physicochemical properties of a drug affect to a large extent its subsequent biological absorption and bioavailability profile. Considerable pharmaceutical interest is therefore directed torwards the improvement of drug dissolution characteristics of drugs with low aqueous solubility. This thesis has considered the controlled modification of drug dissolution profiles by means of incorporating low concentrations of hydrophilic polymers by different processes into a host drug substance. In order to examine this approach and its potential use, the physicochemical, solid state, stability and tableting properties of a poorly aqueous soluble drug, phenylbutazone, in alternative polymorphic form and containing low levels of two hydrophilic polymers - hydroxypropyl methylcellulose (H. P. M. C. ) and the surfactant poloxamer 188 - prepared by both conventional crystallisation and spray drying are reported. As an integral nart of the work attempts were mado to identify the different polymorphic forms of phenylbutazone. The 6-form, the cammerdiallý 4- available stable ýorm and the a and s metastable forr. s (nomenclature after Huller, 1978).. were isolated. The a form was found to be unstable on storage. A .7 fold increase in intrinsic dissolution rate was observed for the metastable s-polymorph compared with the stable 6-polymorphic form. The effect of crystallisation rate on the formation of polymorphs of phenylbutazone was studied using a mini-spray dryer, and slower rates of crystallisation were found to favour polymorph formation. The hydrophilic polymers, H. P. M. C. and poloxamer 188 were incorporated by conventional crystallisation and spray drying into the drug crystal. Samples were subjected to a series of tests including differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, and intrinsic dissolution and solubility. When prepared by conventional crystallisation H. P. M. C. was f8und to form a "high energy" complex with phenylbutazone which melted 10 C lower than the parent drug. When prepared by spray drying H. P. M. C. inhibited the formation of the metastable a-polymorph of phenylbutazone. A2 fold increase in intrinsic dissolution rate was observed for crystallised and spray dried samples containing 2% w/w or more added polymer. Poloxamer 188 did not form a complex witý phenylbutazone and unlike H. P. M. C. did not inhibit thejgr gation of the a-polymorph. For both crystallised and spray fo0ld increase in dissolution rate was obtained at polymer levels oý 1% w/w or above. The increase in dissolution has been attributed to facilitated wetting by lowering of interfacial tension rather than through the formation of micelles. The stability of-selected phenylbutazone: polymer samples was tested at elevated temperatures. The stability was found to be affected both by the method of sample preparation and the type of additive. Large breakdowns occurring by a hydrolytic effect were identified for the crystallised phenylbutazone samples containing poloxamer 188. The effects on compact. ion of phenylbu. tazone in alternative form and presence of polymeric additives were studied by compressing samples of similar particle sizes of phenylbutazone as supplied (67form), samples of spray dried phenylbutazone (a-form) and samples containing different concentrations of H. P. M. C. prepared both by conventional crystallisation and spray drying. Compaction data were analysed according to the Heckel relationship and by force transmission ratio as well as from the tensile strengths of prepared tablets. The presence of H. P. M. C. up to 5% w/w concentration in phenylbutazone did not change the mean yield pressure for the crystallised or spray dried samples, although a difference in mean value was observed between the crystallised and spray dried materials, 93.22 MPa and 147.02 MPa respectively. Force transmission was found to be improved for samples containing H. P. M. C. prepared by both techniques and in general, the tablet tensile strengths for crystallised samples containing H. P. M. C. were approximately three times greater than for spray dried samples at equivalent tablet porosity. Differences are attributed to variation in solid state and particulate properties between samples. / Saudi Arabian Government

<p> Hydroxypropyl guar (HPG) is an effective ingredient in lubricant eye drops used by patients with dry eye disease. The overall goal of the work described in this thesis is to understand the physical-chemical properties of HPG in the presence ofmodel surfaces and solutes with view to understanding the behavior of HPG in the tear film. </p> <p> HPG behaviors are complex because borate ions bind to HPG, which converts nonionic HPG into anionic polyelectrolyte, RPG-borate. The borate binding constants are very low, meaning the charges on RPG-borate are labile. Another consequence ofweak binding is that the equilibrium electrolyte concentration with HPG-borate is relatively high. Mathematical models were developed to predict the structure of HPG-borate as functions of pH. </p> <p> This thesis probes the question "When does HPG-borate behave as an anionic polyelectrolyte?" This work shows that HPG-borate exhibits deviant behaviors of an anionic polyelectrolyte: does not interact with cationic surfactants below the CMC; does not interact with lysozyme (cationic protein), and does not adsorb onto cationic liposomes. By contrast, anionic polyelectrolytes such as carboxymethyl guar display generic behaviors. On the other hand, HPG-borate forms polyelectrolyte complexes with cationic polyelectrolytes at low ionic strength and other work from our laboratory has shown that HPG-borate flocculates cationic polystyrene latex. </p> <p> This complex range of RPG-borate behaviors was rationalized by proposing that the labile nature ofthe charge groups means that the charge density on RPG-borate is regulated by the local electrostatic environment. Near a cationic surface HPG-borate charge density increases whereas near an anionic surface the charge density is lower. </p> <p> Anionic liposome interactions with HPG-borate were characterized. HPG concentrations close to clinical levels induced depletion flocculation ofthe anionic liposomes. This is the first example we have found depletion interactions were proposed for the tear film. </p> <p> To summarize the main implications for the ophthalmic application of HPG are: 1) under ophthalmic conditions HPG-borate behaves as a nonionic water soluble polymer; 2) RPG-borate will adsorb onto hydrophobic domains but will not interact with lysozyme; 3) depletion interactions are important and have the potential to stabilize the lipid layer and destabilize emulsion droplets and other dispersed species in the tear film. </p> / Thesis / Doctor of Philosophy (PhD)

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