Nifedipine is a photolabile calcium channel antagonist which undergoes rapid photodegradation in solution and in solid-state with an accompanying loss of pharmacological potency and clinical efficacy. Nifedipine photostabilization which has received considerable attention has principally been achieved by physical obscuration and through the use of colourants or ultraviolet light absorbers incorporated into liquid preparations, translucent packaging materials, gelatin capsules and/or their fillings and tablet coatings or cores. This study was initiated by a South African pharmaceutical manufacturer in response to increasing evidence that cyclodextrin (CD) inclusion complexation may improve drug photostability. The brief was to evaluate the potential of selected cyclodextrins as photoprotecting agents for nifedipine in the solid-state. Areas of investigation included i) quantitative method development and validation for selective determination of nifedipine, ii) phase solubility studies to establish the solubilizing potential and complexing tendencies of selected cyclodextrins, iii) preparation of solid-state nifedipine - cyclodextrin binary systems using an industrially applicable method, iv) pre-formulation photostability studies to determine the effects of the cyclodextrins on solid-state nifedipine photostability and v) comparative in vitro dissolution assessments of nifedipine, the nifedipine - cyclodextrin binary systems and their respective physical mixtures. Phase solubility studies demonstrated that soluble nifedipine - cyclodextrin complexes were formed in aqueous solution, but the magnitude of the interactions were generally low as reflected by the calculated stability constants which decreased in the rank order, heptakis (2,6-dimethyI)-β-CD (DM-β-CD) > randomly methylated-β-CD (RM-β-CD) > β-CD ≈ 2-hydroxypropyl-β-CD (2HP-β- CD) > γ-CD ≥ 2-hydroxypropyl-γ-CD (2HP-γ-CD). An industrially applicable kneading method yielded binary systems with spectral and thermal characteristics similar to the respective physical mixtures, implying weak solid-state inclusion complexation. Preparation of an amorphous nifedipine - RM-β-CD product using a heating method is reported. A 1.7- and 1.9-fold improvement in solid-state nifedipine photostability was observed for I : 1 molar ratio β-CD and γ-CD kneaded products, respectively, when exposed to window-filtered daylight and could be attributed to changes in opacity of the crystalline kneaded products. The remaining cyclodextrins produced negligible nifedipine photostabilization. Nifedipine in vitro dissolution was improved considerably from γ-CD and RM-β-CD .kneaded products as a result of increased nifedipine wettability, solubility and reduced particle size. iii

The traditional approach of Quality by Testing (QbT) limits the assurance of product quality to in-process and post-production testing. To overcome these limitations, a more proactive and systematic means to product development and optimisation is required. Quality by Design (QbD) is an example of such an approach which focuses on understanding the product and its manufacturing process and emphasises that quality should be built into the product and not merely tested. The study aims to optimise ethionamide tablets, an immediate release oral solid dosage form using QbD.

Orientador: Anselmo Gomes de Oliveira / Orientador: Marcela R. Longhi / Banca: Elba I. Buján / Banca: Santiago Palma / Banca: Palmira Daflón Gramião / Programa de Pós Graduação doutorado em Ciências Químicas / Resumo: Não disponível / Abstract: Not available / Doutor

University of Macau / Institute of Chinese Medical Sciences

Thesis (MTech (Chemistry))--Cape Peninsula University of Technology, 2015. / Solvatomorphism of an active pharmaceutical ingredient (API) is one of the most studied areas in pharmaceutical science. Since APIs are exposed to solvents during many stages of their production, knowledge of the consequences from such exposure is essential. Salt formation has been known to improve some physicochemical properties of an API. Amongst these properties, API solubility is one of the most important characteristics as their use in the market is determined by this feature. Research presented here investigated the solvates and salts of mefenamic acid (MA) and tolfenamic acid (TFA); both representing fenamic acids belonging to a class of non-steroidal anti-inflammatory drugs (NSAIDs). Solvates were obtained by reactions of TFA and MA with the solvents 2-picoline, 3-picoline, 4-picoline, 3-bromopyridine and 3-chloropyridine. A solvate polymorph of MA and 2-picoline was isolated. The salts were obtained by using diethanolamine, ethylenediamine, 1-methylpiperazine, and triethylamine in combination with the fenamic acids. Morpholine formed a salt with TFA, but not with MA. Instead a zwitterionic form of MA was synthesised when the latter was mixed with morpholine. The resulting compounds were characterised and their crystal structures analysed. It was found that the conformation of the acids in the solvate and the salt compounds differed. Moreover, within the solvates, the conformation of the fenamate backbone varied depending on the acid and the solvent used for crystallisation. Although similar solvents were utilized, the structural packing arrangements of TFA solvates were very different from the arrangements associated with MA. The thermal analyses of the salts/solvates were determined by using both thermogravimetry and differential scanning calorimetry. The compounds were further investigated after manual grinding and the preparation of slurries. These preparation methods were successful for most compounds but not for MA•2PIC and (MA-)(EDM+). Instead, the recrystallization, grinding and slurry investigations of MA•2PIC yielded a polymorph of this particular solvate. In the case of (MA-)(EDM+), the PXRD results obtained from both the pulverised and slurry samples were completely different from one another and also from those determined for the starting materials. Generally, the desolvation studies of the MA salts and solvates produced the same crystal form as occurred in the starting material. The exception was (MA-)(TA+) wherein desolvation produced a mixture of two polymorphs of MA.

A obtenção e o estudo de sais orgânicos de megazol constituem a meta deste trabalho. Problemas futuros de formulação poderão surgir em função da dificuldade de solubilização do fármaco em água, o que justifica a necessidade de obtenção dos referidos sais. Alterações na rota de síntese do megazol também foram estudadas, visto ser este a matéria prima do estudo. Observou-se que o megazol pode ser obtido por diferentes caminhos sintéticos e o escolhido foi uma rota já desenvolvida em nosso grupo. Nesta rota foram detectados alguns pontos de estrangulamento tornando-se necessária ativar o grupamento tiólico na alquilação e modificar as condições de nitração do produto alquilado. Quanto aos demais processos envolvidos, parecem não haver necessidade de modificações experimentais. / This work has the purprose of obtainng and studying of some organic salts of megazol. the reason for obtaining is due to the difficulty solubilization of drug in water, carrying problems on formulation. Modification in route of synthesis to obtention of megazol has been studied. The obtention of megazol has been observed and because of this can be in differents synthetic routes, processes and reagents of chemistry of heterociclycs, example imidazoles modifying. It\'s necessary the activation of thiol group in step alhylation, and the nitration of alkylated products simplify the nitratio. There are no need for changes in additional processes.

A obtenção e o estudo de sais orgânicos de megazol constituem a meta deste trabalho. Problemas futuros de formulação poderão surgir em função da dificuldade de solubilização do fármaco em água, o que justifica a necessidade de obtenção dos referidos sais. Alterações na rota de síntese do megazol também foram estudadas, visto ser este a matéria prima do estudo. Observou-se que o megazol pode ser obtido por diferentes caminhos sintéticos e o escolhido foi uma rota já desenvolvida em nosso grupo. Nesta rota foram detectados alguns pontos de estrangulamento tornando-se necessária ativar o grupamento tiólico na alquilação e modificar as condições de nitração do produto alquilado. Quanto aos demais processos envolvidos, parecem não haver necessidade de modificações experimentais. / This work has the purprose of obtainng and studying of some organic salts of megazol. the reason for obtaining is due to the difficulty solubilization of drug in water, carrying problems on formulation. Modification in route of synthesis to obtention of megazol has been studied. The obtention of megazol has been observed and because of this can be in differents synthetic routes, processes and reagents of chemistry of heterociclycs, example imidazoles modifying. It\'s necessary the activation of thiol group in step alhylation, and the nitration of alkylated products simplify the nitratio. There are no need for changes in additional processes.

引子: 共晶技術和納米沉澱技術於近年被廣泛討論能改進藥物性質和提高體內性能。本論文研究旨在將該兩種技術嘗試應用於五種模型藥物中，分別是薑黃素(CUR)，氟比洛芬(FLU)，布洛芬(IBU)，酮洛芬(KET) 和環氧洛芬(LOX)。這些藥物均難溶於水，擁有較差機械性質，相對高的親油性和潛在治療腦退化症的功用。在共晶技術中，藥物將會與煙酰胺(NCT)先溶於在溶劑中，透過蒸發以誘發共晶產生。另一方面，瞬時納米沉澱(FNP)技術會將藥物溶液(包含穩定劑)與反溶劑在封閉衝擊射流混合器(CIJM)或多入口渦旋混合器(MIVM)快速混合，生成納米藥物。 / 方法: 將藥物和NCT溶於乙醇中，應用旋轉蒸發或簡單蒸發生成共晶。透過不同的檢測方法，包括X射線衍射，差示掃描量熱法，熱重分析，吸濕分析，傅立葉變化紅外線光譜，特性溶出速率量度法和壓實分析將共晶檢定。另一方面，利用CIJM或MIVM，藥物在不同的混合速率，溶劑性質，聚乙二醇-聚乳酸(穩定劑)分子重量或藥物對聚合物比的工藝環境下載入於納米粒子中。生產出來的納米藥物會利用動態光散射測定粒徑; 電泳光散射法測定zeta電位; 掃描電子顯微鏡和原子力顯微鏡測定粒子形貌和其表面性質; X-射線光電子能譜測定表面成分; 高效液相色層分析測定載藥量和包封率。 / 結果: 利用旋轉蒸發，高純度的1:1 IBU-NCT 和FLU-NCT 的共晶能成功生成，但KET-NCT和LOX-NCT 共晶則不能獲得。低純度的CUR-NCT 共晶可根據相同技術取得。相比原來藥物而言，IBU-NCT 和FLU-NCT 共晶均有較好的機械性質，抗吸水性和溶解速度。而在FNP研究中，証實了混合速率，溶劑性質，聚乙二醇-聚乳酸(穩定劑)分子重量或藥物對聚合物比均對生產出來的納米粒子的粒徑有重要影響。另外，納米粒子的穩定性可籍添加輔助穩定劑(如PVA)大幅提高。XPS分析証實輔助穩定劑能與在粒子表面的聚乙二醇起相互作用，更佳地保護粒子。而在一系列對四種不同的洛芬藥物的實驗中，多次線性回歸分析指出三種有關藥物的溶液性質(即溶解度，分配係數和酸度系數)會對生成的納米粒子的粒徑和包封率有顯著影響。 / 結論: 將IBU和FLU與NCT結成共晶能同時提高其機械性質，抗吸水性和溶解速度。而在FNP中，優化不同工藝參數能有效控制納米藥物的粒徑，形態，表面性質和穩定性。 / Introduction: In recent years, cocrystallization and nanoprecipitation have gained increasing popularity as viable strategies for improving the pharmaceutical properties and in vivo performance of drugs. The present thesis was aimed at assessing these two approaches for potential applications in pharmaceutical formulation and manufacture with five model drugs, viz. curcumin (CUR), flurbiprofen (FLU), ibuprofen (IBU), ketoprofen (KET) and loxoprofen (LOX). Selection of these drugs for the study was guided mainly by their poor water solubility, poor compactibility, typical drug‘s lipophilicity (log P =3-5), and potential for treatment of Alzheimer‘s disease. Cocrystallization was induced by the attainment of a sufficient supersaturation level through rapid solvent removal from a solution containing the drug and the coformer, nicotinamide (NCT), while flash nanoprecipitation (FNP) was achieved by rapid and homogenous mixing of drug solution (with stabilizer and co-stabilizer if required) with antisolvent in the mixing chamber of a specially designed confined impinging jet mixer (CIJM) or multi-inlet vortex mixer (MIVM). / Methods: Cocrystals were prepared by rotary solvent evaporation or slow evaporation of a solution of drug and NCT in ethanol, and characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetry, moisture sorption analysis, Fourier transform infrared spectroscopy, intrinsic dissolution rate (IDR) measurement and compaction analysis. Polymer-stabilized drug nanoparticles were prepared by FNP using a two-stream CIJM or four-stream MIVM under defined conditions of varying flowrate, solvent type, molecular weight of amphiphilic diblock (PEG-PLA) copolymer (stabilizer), or drug-to-copolymer ratio. The resulting nanoparticles were characterized for particle size by dynamic light scattering; zeta potential by electrophoretic light scattering; particle morphology and surface properties by scanning electron microscopy and atomic force microscopy; surface composition by X-ray photoelectron spectroscopy (XPS); and drug loading and encapsulation efficiency (EE) by high performance liquid chromatography. / Results: Phase-pure 1:1 cocrystals of IBU and FLU with NCT were obtainable by rotary solvent evaporation, but not slow evaporation. Similar solvent removal failed to cause any cocrystal formation for KET and LOX while inducing partial cocrystal conversion for CUR. Both IBU-NCT and FLU-NCT cocrystals displayed enhanced IDR, reduced moisture sorption and improved tabletability compared with the individual profen crystals. FNP studies using the MIVM confirmed the flowrate, solvent type, molecular weight of PEG-PLA copolymer, and drug-to-copolymer mass ratio being important process variables for controlling particle size and particle stability. Particle stability could be enhanced with a hydrophilic co-stabilizer (e.g., PVA). Such co-stabilizers possibly act by binding to the PEG corona at the particle surface to reinforce the protective steric barrier, as substantiated by XPS data. Comparative studies on nanoparticle production by FNP for the four profens indicated that three structure-related intrinsic solution properties of the profens, namely, water solubility, log P and pKa, were important determinants of the particle size and EE of nanoparticles, as determined by multiple linear regression analysis. / Conclusion: Cocrystallization with NCT can simultaneously improve the tableting behavior, hygroscopicity, and dissolution performance of IBU and FLU. Proper optimization of the process variables in FNP is critical to the controlled production of polymer-stabilized drug nanoparticles with consistent properties and storage stability. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Chow, Shing Fung. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 224-247). / Abstracts also in Chinese.

Pulmonary and oral drug administrations are usually the preferred methods of delivery of active pharmaceutical ingredients.Generally,pulmonary drug formulations are more attractive compared to oral formulations since they consist of micron-sized powders with high surface area thus having faster onset of action,as well as minimizing the drug dosage and side effects.Oral insulin formulations,if achievable,would provide an alternative to injectable insulin,as the common drawbacks of injectable insulin are the multiple daily injections and the possibility of skin infections at the injection site. In this study,the feasibility of using dense gas particle processing techniques known as the Aerosol Solvent Extraction System (ASES),Gas Anti-Solvent (GAS)and High-Pressure Media Milling (HPMM)for pharmaceutical processing was assessed.The ASEStechnique,utilizing dense ethane,was employed to prepare insulin-lactose formulations for pulmonary administration whilst the GAS and ASES techniques,utilizing dense CO2,were employed to prepare microencapsulated formulations containing insulin and Eudragit?? S100 for oral administration.Furthermore,the HPMM technique,utilizing dense hydrofluocarbon (HFC)134a/227ea,was employed to prepare suspension Metered Dose Inhaler (MDI)formulations containing budesonide and various surfactants. The Fine Particle Fraction (FPF)of processed insulin without the presence of lactose was found to be 44%.In other words,44% of processed insulin delivered to the impactor stages (excluding the throat and neck)has aerodynamic diameter of less than 5??m.With the addition of lactose as carrier,the FPFof the insulin-lactose (1:1w/w)formulation increased to 64%.The increase in FPFwas attributed to the lower density of lactose particles compared to that of insulin particles to produce an intimate mixture with enhanced powder flowability and aerodynamic performance. Proteins for oral delivery should ideally be formulated with acid-resistant polymer as a protective coating to protect against enzymatic degradation in the stomach.Eudragit?? S100,which is insoluble or almost impermeable at pH 1-4and soluble at pH 5-7,was used to prepare oral insulin formulations.The insulin release at pH 3was sustained by the Eudragit?? S100coating and the encapsulation efficiency of insulin??Eudragit?? S100formulations varied between 6% and 24% depending on the initial drug to polymer ratio. One of the major therapies utilizing metered dose inhaler formulations in the treatment of asthma has been studied using the HPMM process.The HPMM process has been demonstrated to be an efficient milling process for the enhancement of the physical stability and aerodynamic performance of budesonide in HFC-134a/227ea propellant formulations.No significant change in physical stability was observed in the formulations for 2 weeks.

This dissertation is comprised of four distinct formulation sections, which are described below: A novel solid dosage formulation was investigated for achieving zero-order drug release profile by combining tablet shape design and tablet membrane film coating. Verapmail (model drug) was compressed into hydrophilic matrix tablet cores of flat-faced and bi-convex shape, which were encapsulated with membrane controlling film. The hydrophilic tablet core contained hydroxypropyl methylcellulose (HPMC) 15 LV, pectin, and Avecil��. The membrane film coating solution was comprised of deionized water, Opadry��, Surelease�� and talc. The combination of membrane film coating and tablet shape design was found to influence in vitro verapamil release profile towards the zero-order release demonstrated by the commercial Covera HS�� (Pharmacia). An alternative formulation for the commercial Bactroban�� (Smithkline Beacham) ointment 2% was developed. Both the texture and consistency of the new ointment were comparable to the Bactroban�� ointment. The new and the commercial formulations were found to be equivalent in drug release by the Bauer-Kirby test. Mupirocin remained unstable in the new formulation. Mg����� was added to help stabilize mupirocin and was shown to complex with mupirocin by nuclear magnetic resonance (NMR). The modified formulation including Mg����� however failed to stabilize mupirocin. The stability assay results showed an average of 67.2% mupirocin recovery along with 25.2% degradation products. A generic omeprazole formulation was developed, which was comprised of nonpareil core, omeprazole matrix layer, and an enteric locating layer of ammoniated hydroxypropyl methylcellulose phthalate (HPMCP) 55S. The new formulation was gastro-resistant in protecting against omeprazole degradation for up to 2 h, but failed to dissolve as rapidly as the commercial Prilosec�� (Astra Merk) in simulated intestinal fluid. The addition of expotab�� to the enteric coating layer failed to improve omeprazole dissolution rate. A novel hot-melt coating methodology utilizing direct blending technique has been developed. The processing steps for the direct blending hot-melt coating are: (a) Hot-melt system preparation; (b) Dispersion/dissolution of the active ingredient(s) in the hot-melt system; (c) Pre-heating of the coating substrate; and (d) Cooling and congealing of the hot-melt on substrate surface. Immunogenic effect was observed in mice administered with enteric-coated ragweed pollen extract (RPE) alpha fraction by the hot-melt coating encapsulation with direct blending method. The effect was not shown to be statistically significant. / Graduation date: 2003