Natural products are complex mixtures of compounds with therapeutic effects which are often reported to be due to the synergistic action of multiple and sometimes unknown components. Consequently, standardization of these products is complex and a lack of effective quality control (QC) criteria in most countries has led to marketing of commercial products with questionable quality, safety and efficacy (QSE). The aim of this study was therefore to develop qualitative and quantitative analytical methods for use in the QC of Ginkgo biloba solid oral dosage forms. Initially, a micellar electrokinetic chromatography (MEKC) method was developed for the identification of the flavonol glycosides, rutin and quercitrin as well as 3 flavonol aglycones, quercetin, kaempferol and isorhamnetin in crude extracts of 4 Ginkgo biloba solid oral dosage forms using ultraviolet (UV) detection. A reversed-flow cyclodextrin-modified MEKC method was subsequently developed for the simultaneous determination of the aforementioned flavonols as well as ginkgolide A, B, C, J and bilobalide (all positive markers) in Ginkgo commercial products. A non-aqueous capillary electrophoresis (CE) method was also developed for fingerprinting the presence of ginkgolic acids (negative markers) in Ginkgo biloba leaf extracts, which are purported to be associated with toxic properties. This method was also applied to 2 Ginkgo biloba commercial products. Since the flavonols have strong UV absorbing chromophores, a reversed phase high-performance liquid chromatographic (RP-HPLC) method was developed and validated using photo-diode-array (PDA) detection which was then successfully applied to fingerprint commercially available Ginkgo biloba solid oral dosage forms as well as quantify the relevant flavonol markers present in these extracts. Sample preparation was simple, rapid and cost efficient with minimal clean-up and the employment of a minibore column which requires low mobile phase flow rates contributed to the economy of the method. Unlike the conventional QC approach, samples were not hydrolyzed and direct determination of 2 intact flavonol glycosides, together with the usual aglycone markers was facilitated which provided maximal content information for fingerprint comparisons. On the other hand, terpene trilactones possess poor chromophores and an alternative detection method to UV was required in order to obtain suitable sensitivity. RP-HPLC with evaporative light scattering detection (ELSD) was selected for quantification of these non-volatile constituents in Ginkgo dosage forms and this method was deemed suitable for the routine QC analysis of these positive markers in commercial products. Since approximately 33 flavonoids have been identified in Ginkgo biloba leaf extracts, baseline separation using UV/PDA detection normally requires complex gradient programs and long analysis times. In addition, unequivocal identification of the flavonoids with similar UV spectra and elution times cannot be guaranteed. A liquid chromatographic tandem mass spectrometric (LC-MS-MS) method was therefore developed and validated in order to ensure accurate quantification of the selected flavonol marker compounds in Ginkgo commercial products. LC-MS-MS analysis of Ginkgo extracts revealed, in addition to rutin, the possible presence of other quercetin analogues, quercetin-3-Orhamnoside-7-O-glucoside or quercetin-3-O-glucoside-7-O-rhamnoside, previously unreported in Ginkgo biloba leaf extracts or dosage forms. In terms of evaluating the most suitable analytical method for QC, CE shows exceptional potential in the future analysis of Ginkgo biloba dosage forms while HPLC-PDA and HPLC-ELSD are currently the most affordable and practical instruments for the routine analysis of the flavonols and terpenoids, respectively. LC-MS-MS proved to be pivotal for the accurate identification and quantification of the flavonols due to interference by other flavonoid compounds with similar retention times and UV spectra to the peaks of interest. All quantitative and qualitative results revealed large discrepancies in the marker content between the products regardless of which batch was analysed and product labels disclosed little relevant information. Although currently not required by most regulatory agencies, some of the usual quality criteria applied to orthodox medicines was evaluated. In particular, dissolution analysis, disintegration, tablet hardness and weight uniformity were assessed and revealed similar inconsistencies. This thesis emphasises that implementation of effective QC criteria is long overdue and is essential to ensure consistent product QSE of commercially available Ginkgo biloba solid oral dosage forms.

Submitted in fulfillment of the Masters degree in Technology: Community Health Nursing, Durban University of Technology, 2013. / Background One of the major challenges for the Department of Health in South Africa today is inequity and the need to provide quality integrated health care for all its citizens. Primary Health Care (PHC) has been declared as the way to achieve this goal, through the District Health System. Standard Treatment Guidelines (STGs) and the Essential Medicines List (EML) have been developed and are used at PHC clinics and hospitals. This study explored the use of STGs and the EML by professional nurses at PHC clinics in the UMgungundlovu District, KwaZulu-Natal, South Africa. Methods A quantitative descriptive research design was used. Questionnaires were used to collect data from respondents at the PHC clinics. A retrospective review of facility registers kept by the respondents on the rational use of drugs was also carried out by the researcher. Results The findings of the study revealed that the respondents had a good understanding of the use of the STGs and the EML. There was no evidence of polypharmacy, and medications were prescribed according to guidelines. Areas that were suboptimal were related to prescription writing in writing of schedules and routes of medication as indicated in facility records. The results further showed that training on the use of the STGs and EML were inadequate, which implies the need for strengthening of training programmes.

differential scanning calorimetric profile and the generation of much less intense and broader peaks in the powder X-ray diffraction pattern compared to beta-CD. FTIR analysis revealed significant physical interactions between CX oil and beta-CD in the granules, possibly due to complexation. Results from phase solubility measurements and proton nuclear magnetic resonance ( 1H-NMR) analysis of pure 3-butylidenephthalide (3-BDPH), a representative CX component, lend some support for the formation of a 1:1 stoichiometric inclusion complex between 3-BDPH and beta-CD. / Rhizoma chuanxiong (CX), the dried rhizome of Ligusticum Chuangxiong Hort. (Umbelliferae), has been extensively used in mainland China as a traditional herbal medicine for treating cardio-/cerebrovascular diseases and gynecological disorders. However, the active components in CX, which are predominantly essential oils, generally exhibit poor stability (mostly photo-oxidation), high volatility, low aqueous solubility, and extensive gut/hepatic metabolism, all of which can significantly reduce their oral bioavailability and therapeutic efficacy. The present project has investigated the feasibility of utilizing three formulation approaches to circumvent the aforementioned problems associated with the peroral delivery of CX (as crude oil mixture or individual components). / The first approach involved inclusion of CX oil in beta-cyclodextrin (beta-CD) as solid granules using a coprecipitation method optimized with the aid of an orthogonal study design. The resulting CX oil granules were colorless and odorless with a median particle size of 11.38mum; were stable to heat, light and moisture, and readily soluble in simulated gastric and intestinal fluids. The granules were largely amorphous, as evidenced by an absence of the melting endotherm for beta-CD in the formulation could be largely explicated by the complexation behavior and hydration properties of the two polymers blended in different weight percentages, as substantiated by turbidity measurement, viscosity determination and FTIR analysis of the pure polymer mixtures as well as swelling measurement of the formulated tablets. The sustained release behavior of 3-BDPH from the tablet was dependent on the relative proportion of the two polymers present, and could be similarly explained by the changes in hydration and complexation behavior of the polymers during the penetration of aqueous fluid into the tablet matrix. / The second approach involved incorporation of CX oil into surfactant micelles and liquid crystals as a self-emulsifying drug delivery system (SEDDS). An optimal formulation was developed through a judicial choice of excipients (lipids and surfactants/cosurfactant) and their proper combination in the correct proportions, as determined by the spontaneity of the emulsification process and the change in emulsion droplet size. The formulation was readily dispersible in water upon mild agitation, free from unpleasant odor, and stable in soft gelatin capsules for a storage period of at least 12 months under ambient condition. The optimal utilization of the lipid and surfactant blends in defined proportions in the formulation was further substantiated by interfacial tension determination and equilibrium phase analysis. / The third approach involved formulation of 3-BDPH (or crude CX oil) into a sustained-release buccoadhesive tablet, based on a systematic evaluation of the adhesive properties of two polymers (Carbopol 974P and hydroxypropyl methylcellulose K4M) used in the formulation. The adhesive properties of the formulation could be largely explicated by the complexation behavior and hydration properties of the two polymers blended in different weight percentages, as substantiated by turbidity measurement, viscosity determination and FTIR analysis of the pure polymer mixtures as well as swelling measurement of the formulated tablets. The sustained release behavior of 3-BDPH from the tablet was dependent on the relative proportion of the two polymers present, and could be similarly explained by the changes in hydration and complexation behavior of the polymers during the penetration of aqueous fluid into the tablet matrix. / Gao Yuan. / "April 2005." / Adviser: Albert H. L. Chow. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1585. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 193-223). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Quality by Design (QbD) is a systematic approach that has been recommended as suitable for the development of quality pharmaceutical products. The QbD approach commences with the definition of a quality target drug profile and predetermined objectives that are then used to direct the formulation development process with an emphasis on understanding the pharmaceutical science and manufacturing principles that apply to a product. The design space is directly linked to the use of QbD for formulation development and is a multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide an assurance of quality. The objective of these studies was to apply the principles of QbD as a framework for the optimisation of a sustained release (SR) formulation of salbutamol sulphate (SBS), and for the establishment of a design space using Response Surface Methodology (RSM) and Artificial Neural Networks (ANN). SBS is a short-acting ♭₂ agonist that is used for the management of asthma and chronic obstructive pulmonary disease (COPD). The use of a SR formulation of SBS may provide clinical benefits in the management of these respiratory disorders. Ashtalin®8 ER (Cipla Ltd., Mumbai, Maharashtra, India) was selected as a reference formulation for use in these studies. An Ishikawa or Cause and Effect diagram was used to determine the impact of formulation and process factors that have the potential to affect product quality. Key areas of concern that must be monitored include the raw materials, the manufacturing equipment and processes, and the analytical and assessment methods employed. The conditions in the laboratory and manufacturing processes were carefully monitored and recorded for any deviation from protocol, and equipment for assessment of dosage form performance, including dissolution equipment, balances and hardness testers, underwent regular maintenance. Preliminary studies to assess the potential utility of Methocel® Kl OOM, alone and in combination with other matrix forming polymers, revealed that the combination of this polymer with xanthan gum and Carbopol® has the potential to modulate the release of SBS at a specific rate, for a period of 12 hr. A central composite design using Methocel® KlOOM, xanthan gum, Carbopol® 974P and Surelease® as the granulating fluid was constructed to fully evaluate the impact of these formulation variables on the rate and extent of SBS release from manufactured formulations. The results revealed that although Methocel® KlOOM and xanthan gum had the greatest retardant effect on drug release, interactions between the polymers used in the study were also important determinants of the measureable responses. An ANN model was trained for optimisation using the data generated from a central composite study. The efficiency of the network was optimised by assessing the impact of the number of nodes in the hidden layer using a three layer Multi Layer Perceptron (MLP). The results revealed that a network with nine nodes in the hidden layer had the best predictive ability, suitable for application to formulation optimisation studies. Pharmaceutical optimisation was conducted using both the RSM and the trained ANN models. The results from the two optimisation procedures yielded two different formulation compositions that were subjected to in vitro dissolution testing using USP Apparatus 3. The results revealed that, although the formulation compositions that were derived from the optimisation procedures were different, both solutions gave reproducible results for which the dissolution profiles were indeed similar to that of the reference formulation. RSM and ANN were further investigated as possible means of establishing a design space for formulation compositions that would result in dosage forms that have similar in vitro release test profiles comparable to the reference product. Constraint plots were used to determine the bounds of the formulation variables that would result in the manufacture of dosage forms with the desired release profile. ANN simulations with hypothetical formulations that were generated within a small region of the experimental domain were investigated as a means of understanding the impact of varying the composition of the formulation on resultant dissolution profiles. Although both methods were suitable for the establishment of a design space, the use of ANN may be better suited for this purpose because of the manner in which ANN handles data. As more information about the behaviour of a formulation and its processes is generated during the product Iifecycle, ANN may be used to evaluate the impact of formulation and process variables on measureable responses. It is recommended that ANN may be suitable for the optimisation of pharmaceutical formulations and establishment of a design space in line with ICH Pharmaceutical Development [1], Quality Risk Management [2] and Pharmaceutical Quality Systems [3]

L’étude des caractéristiques physico-chimiques du Compritol® (béhénate de glycérol) et du Précirol® (palmito-stéarate de glycérol) a été effectuée. Les méthodes d’évaluation consistaient en la calorimétrie différentielle à balayage, la microscopie sur platine chauffante et la rhéologie dans un rhéomètre capillaire à pression variable. Cette étude a montré une évolution de la structure cristalline de ces deux corps gras en fonction du temps et de la température de stockage. En effet, ces composés, après fusion et refroidissement, « recristallisent » sous une structure partiellement amorphe, qui évolue avec le temps en structure cristalline. Il est également ressorti de cette évaluation que ces deux excipients lipidiques présentent des plages de fusion bien distinctes. Cette caractéristique est conservée lorsqu’ils sont en mélanges binaires. Enfin, ces corps gras se déforment sous l’action de fortes forces de cisaillement à des températures inférieures à leurs plages de fusion. <p>L’utilisation du Compritol® et du Précirol® comme corps gras lipophiles pour former des microbilles à libération prolongée a alors été envisagée. Nous avons procédé moyennant une technique de fabrication simple et rapide appelée « la pelletisation thermoplastique ». Il s’agit d’un procédé en une étape qui met à profit le pouvoir liant des corps gras facilement fusibles et se passe ainsi de l’usage de l’eau ou de solvants organiques. L’appareillage utilisé est de type mélangeur granulateur à haute vitesse. <p>Nous nous sommes basés sur les renseignements fournis par l’étude de préformulation afin d’optimaliser les conditions de fabrication des microbilles. Le contrôle de la température du mélange est très important pour la réussite du procédé de pelletisation thermoplastique. La vitesse du bras du mélangeur, la température de la double paroi et le temps de sphéronisation constituent les paramètres clés pour réussir la pelletisation du mélange. Nous avons mis au point des formulations contenant 15% (m/m) de Précirol® et une quantité croissante de Compritol® variant de 3 à 65 % (m/m). La libération du chlorhydrate de phényléphrine, employé comme agent traceur, a déjà été ralentie pour les formulations contenant 25 % (m/m) de corps gras. Face à ces résultats encourageants, nous avons mis au point des formulations contenant 75 % (m/m) de différents principes actifs (chlorhydrate de ciprofloxacine, théophylline et kétoprofène) et 25 % (m/m) de corps gras. Ces formulations ont abouti à la fabrication de microbilles à libération prolongée. Une étude de stabilité menée sur certaines des formes finies a montré la stabilité des microbilles lipidiques pour autant que le principe actif incorporé dedans ne soit par lui-même facilement dégradable. <p>Afin d’élargir le champ d’application du procédé de fabrication, nous avons mis au point des microbilles flottantes à libération prolongée. Les formulations proposées contiennent comme excipients :les deux corps gras, un mélange effervescent (bicarbonate sodique/ acide tartrique) et du Methocel K100. Leur flottabilité a été prouvée in vitro sur une période de plus de huit heures et In vivo par administration de microbilles de riboflavine flottantes versus non flottantes à des volontaires humains sains.<p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished