Academic literature on the topic 'Drug-excipient compatibility'

Purpose: A new multivariate chemometric approach was developed for fast and economic compatibility determinations of ranitidine hydrochloride (as model drug) with certain pharmaceutical; polymers (Alginate & Chitosan), excipient (Lactose) and intravenous fluids (Dextrose, Ringer & Dextrose/ Ringer). Binary mixtures of the drug and each item were prepared and investigated by chemometric- assisted UV- spectrophotometry as well as by HPLC reference method. Methods: Five drug concentration levels (0.004-0.025mg/ml) of test-mixtures were used and the average drug recovery percent after two and seven days of storage from initial concentration was determined. Physico-chemical techniques including DSC, XRD, & FTIR were also performed to investigate the nature of the observed drug-additive interactions. Results: UV-chemometric and HPLC results showed that ranitidine stability in mixture aqueous solutions appears to be concentration dependent. The ranitidine content remained greater than 90% in alginate & chitosan test mixtures at all used drug concentrations (0.004-0.025mg/ml), while in lactose, dextrose, ringer & dextrose/ringer test mixtures fell below 90% at low drug concentrations (0.004- 0.009mg/ml), which suggests more ranitidine compatibility with alginate & chitosan rather than the other additives. Conclusion: The developed chemometric method, employing UV absorbance data successfully used as simple, rapid, and economic alternative tool in drug-additive compatibility determinations.

Compatibility studies between active drugs and excipients are substantial in the pharmaceutical technology. Thermal analysis has been extensively used to obtain information about drug-excipient interactions and to perform pre-formulation studies of pharmaceutical dosage forms. The objective of the present study was to evaluate the compatibility of the valsartan (VALS) with pharmaceutical excipients of common use including diluents, binders, disintegrants, lubricants and solubilising agents. Thermogravimetry (TG), derivative thermogravimetry (DTG), but especially differential scanning calorimetry (DSC) were used for a first screening to find small variations in peak temperature and/or their associated enthalpy for six drug/excipient mixtures (starch, cross caramelose sodique, microcrystalline cellulose 102, povidone K30, lactose monohydrate and magnesium stearate), which indicate some degree of interaction. Additional methods using Fourier transformed infrared spectroscopy (FT-IR) and X-ray powder diffraction (XRPD) confirmed the incompatibility of VALS with starch, povidone K30, lactose monohydrate and magnesium stearate. Those excipients should be avoided in the development of solid dosage forms.

The aim of the investigation was to develop a less empirical way of selecting an appropriate polymeric stabilising agent that would effectively maintain good dispersibility of a given drug substance with known physico-chemical properties. This was achieved by quantifying the adsorption of different polymers onto a range of drug substances from different solvent environments and to establish which physico-chemical properties of the polymers control their adsorption or non-adsorption onto a particular drug. The pharmaceutical actives, two proprietary compounds SB-223412, SB-204269 and loperamide HCl were investigated. The drugs are particulate, with very poor water solubility. The drug particles were examined using SEM. The mean particle size was 1.1, 1.4 and 1.0µm respectively. The polymeric excipients chosen for this investigation were the water-soluble polymers hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC), gum arabic (GA), guar gum (GG) and lambda-carrageenan (l-carrageenan). The physico-chemical methods developed in this work help improve the current empirical selection of an appropriate polymer in pre-formulation studies. The methods include an initial bottle test screen. The aim of the screen was to establish which polymers were the most effective in producing stable dispersions of the chosen drug substances. The bottle test screen results showed l-carrageenan and HPMC to be effective stabilisers on SB-223412 and loperamide HCl particles respectively. GA, HPMC and 0.15M NaCl l-carrageenan caused partial dispersion on SB-223412, SB-204269 and loperamide HCl respectively. Stable dispersions were monitored by photon correlation spectroscopy (PCS) for changes in particle size after their preparation and also for up to three months thereafter. Samples remained dispersed at three months. The adsorption characteristics of the stabilising and partially stabilising polymers were quantified by the construction of adsorption isotherms under various conditions of pH and ionic strength. All isotherms were low affinity with a pronounced shoulder region followed by a plateau. Generally all stabilising polymers adsorb to approximately the same amount. Clear differences were seen in the amount adsorbed of partial dispersions. The isotherms provided information regarding how much polymer was required to saturate the surface of a given mass of drug and also some insight into the stabilising mechanism. The combined techniques provided very useful qualitative and quantitative information about the physico-chemical, intermolecular and structural properties of pharmaceutical dispersions in a pre-formulation stage.

A modernização dos equipamentos de granulação por via úmida permitiu o desenvolvimento de diversas técnicas a partir do método tradicional. Dentre as técnicas desenvolvidas, a granulação por solidificação de materiais fundidos (GSMF) elimina o uso de solventes e diminui o tempo de processo. O presente trabalho teve por objetivo estudar o processo de granulação por solidificação de materiais fundidos usando um misturador/granulador do tipo high-shear (HSMG) e avaliar a influência das variáveis do processo nas características farmacotécnicas dos granulados e comprimidos obtidos. O artesunato foi escolhido para realização do estudo de granulação devido ao seu alto grau de cristalinidade e instabilidade química. Foi realizado um estudo de compatibilidade fármaco-excipiente usando técnicas de DSC, FTIR associada a técnicas estatísticas multivariadas (PCA e HCA) e cromatografia líquida de alta eficiência. Os parâmetros de HSMG estudados foram o tipo de diluente, a quantidade de PEG 6000 adicionada, o tempo de massificação, a velocidade do misturador e a velocidade do chopper, usando um planejamento experimental fatorial fracionário 25-1. Os granulados obtidos foram avaliados quanto a densidade, propriedades de fluxo e distribuição granulométrica. Os granulados de manitol apresentaram teor de umidade <1% e span de 1,690. Aqueles com lactose apresentaram teor de umidade > 2% e span de 2,814. A velocidade do misturador e do chopper não apresentaram efeitos significativos nas características dos granulados. O manitol foi escolhido como diluente para o artesunato que foi granulado com misturador a 100 rpm e chopper em 1000 rpm seguindo planejamento experimental fatorial completo 32 em duplicata para estudar variáveis de formulação: a razão artesunato/manitol e a quantidade de PEG 6000 adicionada. A quantidade PEG 6000 adicionada aos granulados contribuiu para o aumento da densidade (aparente e compactada) e do tamanho de partícula, e também para a diminuição da friabilidade, da formação de finos e do span. O perfil compressional dos granulados foi determinado graficamente através das curvas força-tempo e força-deslocamento. O tempo de desintegração dos comprimidos obtidos aumentou com a quantidade de artesunato na formulação enquanto a dureza diminuiu. O PEG 6000 aumentou a resistência mecânica e diminuiu o tempo de desintegração. Foram adicionados 2% de croscarmelose às amostras duplicadas e foi observado uma diminuição do tempo de desintegração dos comprimidos obtidos em 70% e o processo de compressão ficou mais uniforme sem alterar outras características do comprimido como resistência mecânica, trabalho útil, trabalho elástico e plasticidade da formulação.
The modernization of the equipment for wet granulation has enabled the development of different techniques from the traditional method. Among the techniques developed, hot - melt granulation eliminates the use of solvents and reduces the process time. The present work aimed to study the process of granulation by solidification of molten materials using a high-shear mixer/granulator (HSMG) and evaluate the influence of process parameters on particle size distribution, flowability and tableting characteristics of material produced. The artesunate was chosen to carry out the granulation study due to its high degree of crystallinity and chemical instability. A drug-excipient compatibility study was performed by DSC, FTIR combined with multivariate statistical techniques (PCA and HCA) and high performance liquid chromatography. The HSMG parameters investigated were the type of diluent, the amount of PEG 6000 added, massification time, the mixer speed and chopper speed, using a fractional factorial experimental design 25-1. Density, flow properties and particle size distribution of the granules were evaluated. The granular mannitol showed moisture content < 1% and span of 1.690. Granular lactose showed moisture content > 2% and span of 2.814. The mixer and chopper speed did not show significant effects on granule characteristics. Mannitol was chosen as more suitable diluent for artesunate. HSMG was carried out with the mixer speed 100 rpm and chopper speed 1000 rpm according to a full factorial experimental design 32 in duplicate to study formulation variables: artesunate/mannitol proportion and the amount of PEG 6000 added. The amount of PEG 6000 added contributed to increase the granules density (bulk and tapped), mean particle size and also to reduce friability, formation of fine particles and span. The granules compressional profile was determined graphically through force-time and force-displacement plots showing differences in work of compaction, compression and elastic recovery. The disintegration time of tablets obtained increased with the amount of artesunate in formulation while the tensile strength decreased. The amount of PEG 6000 increased hardness and decreased disintegration time. To the duplicate samples were added 2% of croscarmellose and a decrease of 70% in disintegration time of tablets was noted and also compression process become more uniform without changing other tablet features as mechanical resistance, compaction, elastic recovery and formulation plasticity.

Os métodos termo-analíticos são ferramentas úteis na avaliação da compatibilidade entre fármacos e adjuvantes, com destaque à calorimetria exploratória diferencial. Neste trabalho foram avaliados a compatibilidade e o comportamento térmico entre a isoniazida e adjuvantes tecnológicos primários usualmente empregados em formas farmacêuticas sólidas. A compatibilidade foi examinada por meio da preparação de misturas físicas binárias do tipo fármaco/adjuvante. Foi investigada também a influência da granulação por via úmida e do processo de compactação para as misturas de isoniazida e adjuvantes com função de material de enchimento e carga e deslizante. A isoniazida apresentou um comportamento térmico não encontrado na literatura. Os adjuvantes avaliados foram: ácido esteárico, amido, celulose microcristalina, crospovidona, croscarmelose sódica, dióxido de silício coloidal estearato de magnésio, glicolato de amido sódico, hipromelose, lactose, manitol, polidona e talco. Para as misturas físicas, a maioria dos adjuvantes mostrou-se compatível com o fármaco em questão. Foram verificadas interações com o ácido esteárico, o glicolato de amido sódico, a lactose, o manitol e a povidona. A isoniazida mostrou a formação de uma mistura eutética com o manitol e de interação química com a lactose. A agregação por via úmida e o processo de compactação não mostraram influências adicionais na compatibilidade das misturas avaliadas. Os resultados observados foram confirmados por métodos não-térmicos como difratometria de raios X, espectroscopia de infravermelho e ressonância nuclear magnética.
Thermo-analytical methods, and specially Differential Scanning Calorimetry, are useful support for the evaluation of compatibility between drug substances and pharmaceutical excipients. In this work were studied the compatibility and the thermal behavior of isoniazid and pharmaceutical excipients, commonly used for the formulation of solid dosage forms. Colloidal silicon dioxide, corn starch, crospovidone, hypromellose, lactose, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, sodium starch glycolate, stearic acid and talc were the excipients employed in these experiments. The compatibility was analyzed testing binary physical drug/excipient admixtures. The effect of wet granulation and compression was also investigated, in this case especially between isoniazid, fillers and lubricant. For almost all excipients no incompatibilities with isoniazid were observed. Interactions were detected when the drug substance was added to stearic acid, sodium starch glycolate, lactose, mannitol and povidone. Isoniazid formed a euthetic mixture with mannitol, whereas a possible chemical reaction occurred between isoniazid and lactose. Wet granulation and compaction of the tested admixtures did not affect the results observed above. These observations were confirmed by non-thermal techniques, such as X-Ray diffractometry, infrared spectroscopy and nuclear magnetic resonance.