Orientador: José Ricardo de Arruda Miranda / Banca: Luciana Aparecida Corá / Banca: Éder Rezende Moraes / Resumo: A administração oral de fármacos é uma prática comum na terapia e as formas farmacêuticas sólidas são amplamente utilizadas. O conhecimento sobre o trânsito de cápsulas e comprimidos no trato gastrointestinal é incompleto. Desse modo, avaliar o trânsito esofágico de farmacêuticas sólidas fornece um entendimento mais profundo sobre os mecanismos que desencadeiam a esofagite induzida por fármacos. Geralmente, os estudos de trânsito esofágico são realizados por meio da cintilografia, manometria e técnicas biomagnéticas, como o SQUID (Dispositivos Supercondutores de Interferência Quântica) e a Biosusceptometria de Corrente Alternada (BAC). A BAC é uma técnica que merece destaque por suas características, acurácia dos resultados obtidos e versatilidade. O objetivo do trabalho foi investigar a influência do tipo e peso da forma farmacêutica no tempo de trânsito esofágico e na velocidade de transporte no esôfago, além de estabelecer parâmetros comparativos entre os métodos cintilográfico e biomagnético empregados, para validar a BAC no estudo de trânsito esofágico de formas farmacêuticas sólidas. Cada um dos seis voluntários que participaram do estudo deglutiu com 50 ml de água cápsulas e comprimidos com 0,5, 0,8 e 1,0 gramas de ferrita, na cintilografia e na BAC. Para o estudo cintilográfico, a radiomarcação das formas farmacêuticas foi feita com 99mTc. Os resultados obtidos mostraram que o tipo e o peso da forma farmacêutica não influenciaram significativamente o tempo de trânsito esofágico e a velocidade de transporte no esôfago, embora os resultados estatísticos apontem para uma variação significativa para um número maior de voluntários. Além disso, uma comparação entre as técnicas permitiu validar a BAC como um método biomagnético para avaliar o trânsito... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Oral administration is a common practice in drug therapy and the solid dosage forms are widely used. Knowledge about esophageal transit of tablets and capsules is incomplete since it have been reported a number of injuries related to drug-induced esophageal damage. Esophageal transit time may be evaluated by employing gammascintigraphy, manometry, and biomagnetic techniques as SQUID and AC Biosusceptometry (ACB). ACB is a non-invasive and radiation free technique which enough versatility for a number of studies related to the gastrointestinal behavior of solid dosage forms. The aim of this work was to investigate the influence of different dosage forms (hard gelatin capsules and tablets) on the esophageal transit time and transport velocity in the esophagus upon to establish a comparison between the Scintigraphy and Biosusceptometry and to validate the ACB as a tool for esophageal transit studies. Six volunteers have participated in the study and they swallowed capsules and tablets with 0.5g, 0.8g and 1.0g of ferrite together 50 ml of water. For scintigraphic study, the dosage forms were labeled with 99mTc. The results showed that the parameters evaluated could not be significantly influenced by the different dosage forms administered. However, it could be observed that the results pointed out to a decrease in the transit time measured for dosage forms with lower weight. We have shown that ACB allowed investigating the influence of dosage forms parameters on the esophageal transit time in healthy volunteers with high spatiotemporal resolution. In summary, this study has allowed introducing the ACB as an alternative technique to investigate the esophageal transit of pharmaceutical dosage forms to understand the factors which could contribute to drug-induced esophageal damages. / Mestre

Submitted by Biblioteca da Faculdade de Farmácia (bff@ndc.uff.br) on 2017-04-03T16:42:21Z No. of bitstreams: 1 Ventura, Danielle Martins [Dissertação, 2011].pdf: 1094934 bytes, checksum: 7f527e246ec0bc1d24d1c492dc672bbe (MD5) / Made available in DSpace on 2017-04-03T16:42:22Z (GMT). No. of bitstreams: 1 Ventura, Danielle Martins [Dissertação, 2011].pdf: 1094934 bytes, checksum: 7f527e246ec0bc1d24d1c492dc672bbe (MD5) / As formas farmacêuticas líquidas são as mais adequadas para uso em pediatria e em pacientes que não conseguem deglutir comprimidos, pois além de apresentarem maior flexibilidade no ajuste da dose, facilitam a administração dos medicamentos. Como a maioria dos medicamentos disponíveis no mercado está na forma de comprimidos e cápsulas, o recurso utilizado no ambiente hospitalar para contornar as necessidades terapêuticas exclusivas de alguns pacientes é a transformação de formas farmacêuticas (TFF). A literatura apresenta poucos estudos relacionados à estabilidade das formulações produzidas através desta prática, fazendo com que ocorra a utilização empírica dessas formulações. O presente trabalho teve como objetivo desenvolver uma formulação de suspensão de Hidroclorotiazida (HCTZ) a partir de comprimidos de diferentes origens, através de TFF, a ser manipulada em ambiente hospitalar. Para tanto, utilizou-se uma formulação proposta por TAGLIARI (2008), estabelecida para a preparação de suspensões de HCTZ a partir insumo farmacêutico ativo, a fim de se avaliar a aplicabilidade desta formulação às suspensões produzidas por TFF. A formulação proposta tem como composição do veículo suspensor: Carboximetilcelulose sódica (CMC-Na) (0,6%), Glicerina (2%), Benzoato de sódio (0,1%) ácido cítrico e água, mostrando-se estável por mais de 120 dias. Neste trabalho, assumiu-se que as preparações decorrentes da prática de TFF são consideradas preparações extemporâneas e portanto, apresentam prazo de validade de 48 horas, sendo este o período determinado para realização dos ensaios de caracterização. Foram utilizados comprimidos de 4 fabricantes diferentes, sendo que para um deles (FA) utilizou-se comprimidos de 2 dosagens, apresentando as seguintes nomenclaturas: FA1(HCTZ 25mg), FA2 (HCTZ 50mg), FB(HCTZ 25mg), FC (HCTZ 25mg) e FD (HCTZ 50mg). Foi realizada a caracterização desses comprimidos, no qual se determinou o peso médio e o teor, segundo compêndios oficiais, e após a trituração dos mesmos, verificou-se a densidade e a granulometria dos pós obtidos. Os comprimidos de FC apresentaram teor acima do preconizado pela Farmacopeia Brasileira. Porém, optou-se por mante-los no estudo, mediante a correção da quantidade de pó a ser utilizada no preparo das suspensões. As suspensões de HCTZ a 2,5mg/mL foram preparadas utilizando CMC-Na a 0,6% (p/v) como agente suspensor. As formulações produzidas foram avaliadas quanto ao volume de sedimentação e redispersibilidade. Os resultados obtidos nestes ensaios indicaram que as suspensões não apresentavam estabilidade física apropriada, sendo necessária a realização da adequação da formulação proposta. Foram preparadas então, suspensões com veículo suspensor contendo diferentes concentrações de CMC-Na (0,2%, 0,3%, 0,4%, 0,5% e 0,6%) para todos comprimidos utilizados na primeira etapa. As preparações obtidas foram analisadas quanto ao volume de sedimentação, redispersibilidade, comportamento reológico e potencial zeta. O teste de volume de sedimentação mostrou grandes diferenças em todas as suspensões estudadas, diferindo na velocidade de sedimentação e no volume de sedimento formado, sendo estes dependentes da concentração do polímero utilizada. A redispersibilidade foi estudada em dois períodos: após 2 e 7 dias de repouso, sendo semelhantes os resultados encontrados nos dois períodos. Neste teste, os resultados apontaram grandes diferenças na redispersão das formulações, indicando que quanto maior concentração do polímero, mais tempo a preparação levou para ficar homogênea. Na análise do comportamento reológico, todas as formulações estudadas apresentaram fluxo não-newtoniano pseudoplástico, mostrando-se dependente da concentração do polímero utilizada. O potencial zeta obtido nestas preparações indicou a que as suspensões apresentaram-se floculadas. As diferenças apresentadas nos testes realizados indicaram que os diferentes excipientes presentes nas formulações dos comprimidos utilizados, interferiram na estabilidade física das preparações, não sendo possível estabelecer uma formulação a ser utilizada para todos os comprimidos, numa preparação obtida por TFF. Diante disso, foi eleita a formulação de melhor estabilidade física para cada comprimido estudado, e procedeu-se a analise do teor destas formulações. Para tanto, utilizou-se a metodologia analítica farmacopeica, que demonstrou ser especifica, linear, exata, precisa e robusta, dentro das condições experimentais estudadas. As formulações produzidas a partir de TFF apresentaram teor dentro do critério de aceitação proposto / The liquid dosage forms are suitable for use in children and in patients who can’t swallow pills, because it have greater flexibility in dose adjustment and ease the administration of medicines. Like most drugs on the market is in the form of tablets and capsules, the resource used in hospitals to circumvent the unique therapeutic needs of some patients is the transformation of pharmaceutical forms (TPF). The literature contains few studies related to the stability of the formulations produced by this practice, allowing it to empirical use of these formulations. This study aimed to develop a suspension formulation of hydrochlorothiazide (HCTZ) from tablets of different sources through TPF, to be manipulated in a hospital environment. For this purpose, we used a formulation proposed by Tagliari (2008), established for the preparation of suspensions of HCTZ from active pharmaceutical ingredient, in order to evaluate the applicability of this formulation produced by TFF. The proposed formulation has the composition of the vehicle hanger: sodium carboxymethylcellulose (CMC-Na) (0.6%), glycerin (2%), sodium benzoate (0.1%) citric acid and water, being stable for more of 120 days. In this work, it was assumed that the preparations from the practice of TFF preparations are considered untimely and therefore have shelf life of 48 hours, this being the period of time to achieve the characterization tests. The tablets were used from four different manufacturers, and for one (FA) was used two doses of pills, with the following classifications: FA1 (HCTZ 25 mg), FA2 (HCTZ 50 mg), FB (HCTZ 25 mg), FC (HCTZ 25mg) and FD (HCTZ 50 mg). We performed the characterization of these tablets, which determined the weight and content, according to official compendia, and after grinding the same, there was the density and particle size of powders obtained. FC tablets showed above the level recommended by the Brazilian Pharmacopoeia. However, it was decided to keep them in the study, by correction of the amount of powder to be used in the preparation of suspensions. Suspensions of HCTZ to 2.5 mg/mL were prepared using CMC-Na 0.6% (w/v) as an agent hanger. The formulations produced were evaluated for the amount of sedimentation and redispersibilidade. The results from these tests indicated that the suspensions had no proper physical stability, being necessary to perform the suitability of the proposed formulation. Were then prepared, with vehicle suspensions suspensor containing different concentrations of CMC-Na (0.2%, 0.3%, 0.4%, 0.5% and 0.6%) for all tablets used in the first step. The preparations obtained were analyzed for the amount of sedimentation, redispersibilidade, zeta potential and rheological behavior. The sedimentation volume test showed significant differences in all the suspensions studied, differing in sedimentation rate and volume of sediment formed, which are dependent on the concentration of the polymer used. The redispersibilidade was studied in two periods: after 2 and 7 days of rest, the results were similar in both periods. In this test, the results showed great differences in the redispersion of the formulations, indicating that the higher concentration of the polymer, the preparation took more time to be homogeneous. In the analysis of rheological behavior, all the formulations studied showed non-Newtonian pseudoplastic flow, being dependent on the concentration of the polymer used. The zeta potential obtained in these preparations indicated that the suspensions had to flocculate. The differences in the tests indicated that the different excipients present in formulations of tablets used, influenced the physical stability of the preparations, it is not possible to establish a formulation to be used for all tablets, a preparation obtained by TPF. Thereat, the better physical stability for each formulation studied was elected, and we proceeded to analyze the content of these formulations. For this purpose, we used the analytical methodology pharmacopoeia, which proved to be specific, linear, accurate, precise and robust, within the experimental conditions studied. The formulations produced from TPF content presented within the proposed acceptance criterion

Over the past few decades many researchers have investigated the utility of in vitro - in vivo correlations for the assessment of dosage forms. These investigations are, however, dependent on reproducible dissolution data and well conducted biostudies in order to establish meaningful and robust correlations. Despite the fact that the establishment of such correlations is perhaps idealistic, considerable interest has still been shown in this area of research. Various Controlled/Modified Release Dosage Forms (CMRD's) of theophylline, a weakly basic drug, and indomethacin, a weakly acidic drug, were assessed in order to establish in vitro - in vivo correlations. Dissolution rate studies were carried out using either the USP basket or paddle apparatus. The dissolution rate studies were conducted in a range of dissolution media of varying pH. Bioavailability studies were conducted on the dosage forms used by the Biopharmaceutics Research Institute at Rhodes University. The results of these biostudies were kindly made available for use in this research project. Type A correlations were established using a mathematical simulation process whereby expected in vivo responses are simulated and compared to actual profiles obtained for the dosage forms. In order to perform the simulations the dissolution rate profiles were stripped and using linear regression and the methods of residuals the dissolution rate order and the relevant dissolution rates were obtained. The results of the s imulations indicated that the in vivo serum concentration-time curves could be accurately predicted for the theophylline dosage forms but to a lesser extent, for the indomethacin formulations. The dissolution rate studies indicated that the paddle method is a suitable method for dissolution rate studies of theophylline CMRD's, although it appeared that the optimum pH of the dissolution medium was formulation dependent. Dissolution rate studies conducted on indomethacin formulations indicated that the USP specified basket method for extended-release indomethacin formulations was not able to distinguish between two formulations which exhibited different in vivo profiles. The conversion to the paddle method was, however, able to highlight the differences between these formulations. The use of three dimensional topographs to depict dissolution rate profiles was demonstrated for formulations of both theophylline and indomethacin. The topographs enabled the successful differentiation between bioinequivalent formulations. The dissolution rate profiles were also fitted to the Wei bull equation and the parameters obtained from this were compared to the Weibull parameters obtained from the in vivo absorption plots obtained using the Wagner-Nelson method. The results indicated that the Weibull function was suitable to describe both the in vivo and in vitro data. The following recommendations for the preformulation dissolution studies of weakly acidic and weakly basic drugs are proposed. The dissolution rate studies of weakly acid drugs, such as indomethacin, should be carried out over a range of pH utilising the paddle apparatus. Three dimensional topographs based on the dissolution data should be constructed and used as a comparative tool for different formulations. Based on these comparisons the appropriate formulation can then be selected for a pilot scale in vivo bioavailability study. The dissolution rate studies of weakly basic drugs, such as theophylline, should be carried out over a range of pH utilising the paddle apparatus. The dissolution data should then be used to simulate the expected in vivo profile and on this basis the appropriate formulation selected for a pilot scale bioavailability study. The above approach to the preformulation studies of new CMRO's would allow for the more careful selection of new dosage forms and could thus eliminate costly and unnecessary bioavailability studies performed on inferior formulations.

The dissolution profiles of eight lots of paracetamol tablets representing seven different tablet brands are determined in a USP rotating basket assembly and a stationary basket-rotating paddle apparatus. The in vitro data are expressed in terms of dissolution parameters and inter-tablet differences are assessed statistically using analysis of variance (ANOVA) and the Scheffe test. Highly significant differences are observed between a number of the tablets at the 95% confidence level. Representative tablets from the dissolution rate study and a control dose of paracetamol dissolved in water are subsequently investigated in a 4 x 4 latin square design bioavailability trial. Serum and urine samples are collected and assayed for paracetamol alone (serum) and together with its metabolites (urine) by means of high pressure liquid chromatography. The in vivo data are expressed in terms of bioavailability parameters and differences between the test doses are assessed by means of ANOVA. No significant differences are observed between the dosage forms at the 95% confidence level.

Numerous experiments in recent years have indicated differences in the bioavailability of corticosteroids from seemingly identical topical dosage forms. The human blanching assay was utilized in this study to assess the comparative blanching activities of various locally manufactured proprietary corticosteroid preparations. The first experiment was performed to assess the relative blanching activities of six semi - solid preparations containing the same concentration of betamethasone 17-valerate. The preparations used were Betnovate cream and ointment, Persivate cream and ointment and Celestoderm-V cream and ointment. This was followed, in the second experiment, by the investigation of the blanching activities of two lotions containing betamethasone 17-valerate (Betnovate and Celestoderm-V) and a lotion containing betamethasone 17,21- dipropionate (Diprosone). The third experiment involved a study of six semi-solid proprietary corticosteroid-containing formulations, viz. Dermovate (clobetasol propionate) cream and ointment, Betnovate (betamethasone 17-valerate) cream and ointment and Eumovate (clobetasone butyrate) cream and ointment. This investigation was prompted by claims in advertisements in the medical media that Dermovate is therapeutically more efficacious than Betnovate which is more efficacious than Eumovate. The penultimate experiment in this study served the purpose of finding a corticosteroid-containing preparation that falls into the moderately potent group of corticosteroid formulations, as described in the United Kingdom MIMS. This preparation was used in the final experiment which was undertaken to ascertain the potency category of Florone (diflorasone diacetate) cream and ointment.

Importance: Polymorphic expression of drug metabolizing enzymes affects the metabolism of antidepressants, and thus can contribute to drug response and/or adverse events. Pregnancy itself can affect CYP2D6 activity with profound variations determined by CYP2D6 genotype. Objective: To investigate the association between CYP2D6 genotype and the risk of antidepressant discontinuation, dosage modification, and the occurrence of maternal CYP2D6, Antidepressants, Depression during pregnancy. Setting: Data from the Organization of Teratology Information Specialists (OTIS) Antidepressants in Pregnancy Cohort, 2006-2010, were used. Women were eligible if they were within 14 completed weeks of pregnancy at recruitment and exposed to an antidepressant or having any exposures considered non-teratogenic. Main Outcomes and Measures: Gestational antidepressant usage was self-reported and defined as continuous/discontinued use, and non-use; dosage modification was further documented. Maternal depression and anxiety were measured every trimester using the telephone interviewer-administered Edinburgh Postnatal Depression Scale and the Beck Anxiety Inventory, respectively. Saliva samples were collected and used for CYP2D6 genotype analyses. Logistic regression models were used to calculate crude and adjusted odds ratios (OR) with 95% confidence intervals. Results: A total of 246 pregnant women were included in the study. The majority were normal metabolizers (NM, n = 204, 83%); 3.3% (n = 8) were ultrarapid metabolizers (UM), 5.7%(n = 14) poor metabolizers (PM), and 8.1%(n= 20) intermediate metabolizers (IM). Among study subjects, 139 women were treated with antidepressants at the beginning of pregnancy, and 21 antidepressant users (15%) discontinued therapy during pregnancy. Adjusting for depressive symptoms, and other potential confounders, the risk of discontinuing antidepressants during pregnancy was nearly four times higher in slow metabolizers (poor or intermediate metabolizers) compared to those with a faster metabolism rate (normal or ultrarapid metabolizers), aOR = 3.57 (95% CI: 1.15-11.11). Predicted CYP2D6 metabolizer status did not impact dosage modifications. Compared with slow metabolizers, significantly higher proportion of women in the fast metabolizer group had depressive symptomin the first trimester (19.81 vs. 5.88%, P = 0.049). Almost 21% of treated women remained depressed during pregnancy (14.4% NM-UM; 6.1% PM-IM). Conclusions and Relevance: Prior knowledge of CYP2D6 genotype may help to identify pregnant women at greater risk of antidepressant discontinuation. Twenty percent of women exposed to antidepressants during pregnancy remained depressed, indicating an urgent need for personalized treatment of depression during pregnancy.

Une variation du nombre de copies des gènes du chromosome 21 humain (HSA21) entraine des anomalies morphologiques et physiologiques d’un grand nombre d’organes chez les patients. La Trisomie 21, ou syndrome de Down et les monosomies partielles du HSA21 conduisent à des phénotypes complexes et variables. Afin d’identifier les gènes du HSA21 sensibles aux effets de dose, nous avons développé le modèle de monosomie Ms1Yah, pour la région Prmt2-Col6a1 du chromosome murin 10 (MMU10). L’analyse de ce modèle a montré que les souris Ms1Yah développent une altération des réponses inflammatoire et pulmonaire suite à une instillation de lipopolysaccharide (LPS). L’analyse, par Q-PCR, de l’expression des gènes de la région a mis en évidence deux gènes candidats : Prmt2 et S100B. Les lignées déficientes pour ces gènes ont été utilisées pour tester l’implication de Prmt2 et S100B dans la modification de la réponse inflammatoire et pulmonaire en réponse au LPS. Ces travaux ont montré d’une part que Prmt2 intervient dans la régulation de l’expression des cytokines pro-inflammatoires TNF-α et IL-6 de façon dose dépendante, via son rôle inhibiteur de la signalisation NF-κB. D’autre part, S100B ne semble pas intervenir dans la réponse inflammatoire induite par le LPS, alors que son inactivation entraîne une diminution de l’hyper réponse des voies aériennes (HRA) de façon dose dépendante. La réponse inflammatoire serait la résultante du croisement de deux voies de signalisation : LPS-TLR4-NF-κB-Prmt2 et S100B-RAGE-NFκB. Il faudrait que la voie Prmt2 soit en défaut pour observée un effet de S100B dans l’inflammation. L’injection d’un anticorps anti-S100B chez des souris B6 favorise une diminution de l’HRA induite par l’instillation de LPS. L’analyse préliminaire de l’utilisation de cet anticorps dans un modèle d’asthme montre là encore une capacité à diminuer l’HRA pour les doses les plus fortes de métacholine, ce qui laisse entrevoir le potentiel thérapeutique d’une telle molécule. / A copy number variation of genes from human chromosome 21 (HSA21) leads to morphological and physiological anomalies of a great number of organs among patients. Trisomy 21 or Down’s syndrome, and partial monosomy of the HSA21 lead to complex and variable phenotypes. In order to identify dosage sensitive genes, we developed a model of monosomy for the Prmt2-Col6a1 region of the murine chromosome 10 (MMU10). The analysis of this model showed that the Ms1Yah mice develop an alteration af the inflammatory and pulmonary responses after an instillation of LPS. The analysis, by Q-PCR, of the expression of the genes from the Prmt-2Col6a1 area pinpointed two genes as candidates: Prmt2 and S100B. The defectives lines for these genes were used to test the implication of Prmt2 and S100B in the modification of the inflammatory and pulmonary answer after LPS stimulation. This work showed on one hand that Prmt2 is involved in the regulation of the expression of the pro-inflammatory cytokines TNF-α and IL-6 in a dose dependant manner, via its inhibitor role in the NF-κB signalization. On the other hand, S100B does not seem to be involved in the inflammatory response induced by the LPS, whereas its inactivation induces a reduction in the hyper response of the airway, in a dose dependant manner. The inflammatory response would be the consequence of the crossing of two ways of signalization: LPS-TLR4-NF-κB-Prmt2 and S100B-RAGE-NF-κB. It would be necessary that the Prmt2 ways be defective to observe an effect of S100B in inflammation.The injection of an anti-S100B antibody in B6 mice showed a reduction in the HRA induced by an instillation of LPS. The preliminary analysis of the use of this antibody in a murin asthma model support its capacity to decrease the HRA for the strongest amounts of metacholin, showing the therapeutic potential of the molecule.

No description available.

Many Active Pharmaceutical Ingredients (API) such as the antiviral agent famciclovir (FCV) are required for paediatric treatment but are not commercially available in age-appropriate dosage forms. It is common practice to prepare oral liquid dosage forms using commercially available tablets, capsules or powdered API and then dispersing or dissolving the crushed and/or powdered materials in a vehicle that the patient can swallow. Vehicles that are commonly used for this purpose include methylcellulose, syrup or combinations of these carriers where possible or commercially available suspending agents such as Ora-Sweet®, if available, can be used. However, several critical factors are overlooked when manufacturing extemporaneous formulations including, but not limited to, physical and chemical properties of the API, excipients, compatibility, stability and bioavailability issues. A stability-indicating High Performance Liquid Chromatography (HPLC) method for the analysis of FCV was developed and validated according to the International Conference on Harmonization (ICH) guidelines. The method is sensitive, selective, precise, accurate and linear over the concentration range 2-120 μg/ml. The stability of 25 mg/ml FCV formulations was assessed in vehicles manufactured from syrup simplex, hydroxypropyl methylcellulose (HPMC), Ora-Sweet® and an aqueous buffer (pH 6) following storage at 25 °C/60% RH and 40 °C/75% RH over six (6) to eight (8) weeks. The shelf life of the products was calculated as the longest period of storage for approximately 90% of the added FCV to be recovered. Formulations were manufactured using syrup simplex or HPMC with methylparaben and propylparaben individually or in combination and with sodium metabisulphite, ascorbic acid or citric acid as antioxidants. The resultant products were subject to quality control analysis for API content, viscosity, pH and appearance and the resultant data were subject to statistical analysis. The degradation rates were calculated for each product and a degradation profile plotted. The degradation rates of FCV in extemporaneous formulations were compared to those of FCV manufactured using a commercially available suspending agent and a buffered vehicle. FCV undergoes major degradation in the presence of sucrose, as observed for formulations in which the vehicle was syrup and Ora-Sweet®. FCV was found to be most stable when dissolved/dispersed in an HPMC vehicle incorporating sodium metabisulphite and a combination of parabens. The formulation that exhibited the maximum stability was manufactured using an aqueous solution buffered to pH 6. Due to the enhanced stability of FCV when added to a buffered vehicle a formulation in which an HPMC vehicle buffered to pH 6 with sodium metabisulphite, methylparaben and propylparaben was selected for optimisation using a Central Composite Design approach (CCD). In this way it was possible to establish a relationship between input variables such as pH, % w/v HPMC, % w/v antioxidant and % w/v preservative and the responses selected for monitoring by means of response surface modelling. A quadratic model was found to be the most appropriate to describe the relationship between input and output variables. Thirty batches of product were randomly manufactured according to the CCD and analysed to establish the stability in respect of viscosity, pH and the amount of FCV remaining following storage and the data were fitted to models using Design-Expert® software. A correlation between input variables and the responses was best described by a quadratic polynomial model. Analysis of Variance indicated that the response surface models were significant (P-value < 0.0001). The pH to which a FCV formulation was buffered was the most significant factor to effect the % drug content and the ultimate pH of the formulation, while the % w/v HPMC had the most significant effect on the viscosity of the product. The optimum composition for the manufacture of an oral liquid FCV formulation was predicted using the optimisation function of the Design-Expert® software. A low % error of prediction was established, indicating that the model is robust and that RSM is an appropriate formulation optimisation tool as it has a high prognostic ability. A liquid FCV formulation was developed, optimised and found to be suitable for its intended purpose. However further optimisation is required in respect of colourants, sweeteners and/or flavourants. The approach followed is useful in ensuring the development of quality products and can be applied in future.

No description available.