Pharmaceutical Solid Forms Research Articles

QUANTIFICATION OF PYRITINOL IN SOLID PHARMACEUTICAL FORMULATION BY HIGH-PERFORMANCE THIN-LAYER CHROMATOGRAPHY-ULTRAVIOLET DETECTION AND SELECTIVITY EVALUATION BY MASS SPECTROMETRY

A high-throughput method for pyritinol quantification in solid pharmaceutical formulation was developed. Chromatography was performed on silica gel 60 F254 HPTLC plates using the mixture dichloromethane – methanol – formic acid 9:1:1 (v/v/v) as mobile phase. Detection was carried out by UV absorbance at 300 nm. Calibration showed a polynomial regression with a determination coefficient (R2) of 0.9992. For chromatography, repeatability (relative standard deviation, RSD) and intermediate precision (RSD) in matrix were 0.4% and 3.0%, respectively. Recoveries of spiked samples at three levels ranging from 98.5 to 101.9% with intermediate precisions of RSD 3.7 to 4.7%. Limits of detection and quantification were 0.6 and 2.0 μg mL−1 (6 and 20 ng/band), respectively. The method capacity to detect degradation products and/or byproducts within routine conditions of analysis was evaluated through forced degradation processes. Selectivity was evaluated determining the peak purity by UV-spectrophotometry, which showed correlation coefficients (r) > 0.9997. Additionally, peak identity and purity was confirmed by mass spectrometry. The mass spectra showed just pyritinol ions at m/z 369 [M + H]+ and 391 [M + Na]+ being acquired directly from the sample bands by an elution-based interface. Considering the validation results, reduced analysis cost, accelerated analysis time, and high throughput capacity, this simple, yet reliable planar chromatographic method is a good alternative for pyritinol analysis in pharmaceutical formulations.

Drug Delivery Systems for Local Anesthetics

Although technological innovations in the area of drug delivery claim for varied benefits, increasing the drug therapeutic index for human clinical application is the main goal pursued. Drug delivery systems for local anesthetics (LA) have attracted researchers due to many biomedical advantages associated to their application. Formulation approaches to systemically deliver LA include the encapsulation in liposomes, complexation in cyclodextrins, association with biopolymers and others carrier systems. Topical delivery systems for LA are characteristically composed by a diversity of adjuvants (viscosity inducing agents, preservatives, permeation enhancers, emollients,) and presentations such as semisolid (gel, creams, ointments), liquid (o/w and w/o emulsions, dispersions) and solid (patches) pharmaceutical forms. The proposed formulations aims to reduce the LA concentration used, increase its permeability and absorption, keep the LA at the target site for longer periods prolonging the anesthetic or analgesic effect and, finally, to decrease the clearance, local and systemic toxicity. This review deals with the innovations pertaining to formulations and techniques for drug-delivery of topical and injectable local anesthetics, as described in recent patents.

Spectrophotometric and chromatographic determination of omeprazole in pharmaceutical formulations

The purpose of this study was to determine the stability of the pH sensitive drug, omeprazole, within different solid oral pharmaceutical formulations and to determine whether the addition of antacid and surfactant agents, at varying concentrations, influenced drug stability and release. Spectrophotometric and chromatographic techniques were used for evaluation purposes, giving good results concerning linearity, precision and specificity within the range of concentrations used in this study. However, the results show that the degradation products of omeprazole interfere with spectrophotometric evaluation, making this technique insufficiently selective for omeprazole. On the other hand, liquid chromotography proved to be more sensitive, accurate and precise. Additionally, in an attempt to improve the administration form of the drug, an extemporaneous suspension was designed, which after evaluation proved to be a satisfactory administration vehicle. The best formulation of omeprazole studied is: omeprazole: 0.5%; corn starch 34.2%; aluminum hydroxide 26%; magnesium hydroxide 13%; simple syrup 24.8%; SDS 1%.

Thermal analysis and compatibility studies of prednicarbate with excipients used in semi solid pharmaceutical form

Differential Scanning Calorimetry (DSC), thermogravimetry/derivative thermogravimetry (TG/DTG) and infrared spectroscopy (IR) techniques were used to investigate the compatibility between prednicarbate and several excipients commonly used in semi solid pharmaceutical form. The thermoanalytical studies of 1:1 (m/m) drug/excipient physical mixtures showed that the beginning of the first thermal decomposition stage of the prednicarbate (Tonset value) was decreased in the presence of stearyl alcohol and glyceryl stearate compared to the drug alone. For the binary mixture of drug/sodium pirrolidone carboxilate the first thermal decomposition stage was not changed, however the DTG peak temperature (Tpeak DTG) decreased. The comparison of the IR spectra of the drug, the physical mixtures and of the thermally treated samples confirmed the thermal decomposition of prednicarbate. By the comparison of the thermal profiles of 1:1 prednicarbate:excipients mixtures (methylparaben, propylparaben, carbomer 940, acrylate crosspolymer, lactic acid, light liquid paraffin, isopropyl palmitate, myristyl lactate and cetyl alcohol) no interaction was observed.

The modified outflow funnel — A device to assess the flow characteristics of powders

Flow regulators are added to solid pharmaceutical formulations to improve the flow properties of powder mixtures. During the blending process the glidants adsorb successively at the surface of the host particles and thus lead to a reduction of attractive forces. A large variety of flow additives based on silicon dioxide is commercially available, but not all glidants are just as well suited for each technological problem or each cohesive bulk powder. To assess the improvement of the flowability parameters caused by a glidant a classification system and an adequate measuring device is needed. We would like to present a new measuring device to evaluate the flow enhancing potency of glidants. The modified outflow funnel features a stirrer that acts in the region of bulk arches obstructing the outflow process of a cohesive powder. By destruction of the bulk arches powder outflow is enabled and the time needed for emanation can be measured as a parameter of the flow properties. In addition other measuring parameters like the force needed to destroy the bulk arches are capable to evaluate the flowability of the powder mixture. Binary powder mixtures consisting of corn starch and flow regulator were blended in a Turbula® mixer for a defined period of time. The flow regulators were represented by fumed silica and a selection of various types of SIPERNAT ® precipitated silica provided by Evonik Degussa GmbH, Hanau, Germany. Flowability parameters of the mixtures were characterized with a modified outflow funnel, Hausner Ratio and a shear tester.

Precipitated silica as flow regulator

Flow regulators are added to solid pharmaceutical formulations to improve the flow properties of the powder mixtures. The primary particles of the flow regulators exist in the form of huge agglomerates which are broken down into smaller aggregates during the blending process. These smaller aggregates adsorb at the surface of the solid's grains and thus diminish attractive Van-der-Waals-forces by increasing the roughness of the host's surface. In most cases amorphous silica is used as flow additive but material properties like particle size or bond strength influence the desagglomeration tendency of the agglomerates and thus the flow regulating potency of each silica. For some silica types we will show that the differences in their flow regulating potency are due to the rate and extent by which they are able to cover the surface of the host particles. Binary powder mixtures consisting of a pharmaceutical excipient and an added flow regulator were blended in a Turbula ® mixer for a defined period of time. As pharmaceutical excipient corn starch was used. The flow regulators were represented by a selection of amorphous silicon dioxide types like a commercial fumed silica and various types of SIPERNAT ® precipitated silica provided by Evonik-Degussa GmbH, Hanau, Germany. Flowability parameters of the mixtures were characterized by means of a tensile strength tester. The reduction of tensile strength with the blending time can be correlated with an increase in fragmentation of the flow regulator.

N‐Methylation and N‐Formylation of a Secondary Amine Drug (Varenicline) in an Osmotic Tablet

Significant degradation of the amine-based smoking cessation drug varenicline tartrate in an early development phase osmotic, controlled-release (CR) formulation yields predominantly two products: N-methylvarenicline (NMV) and N-formylvarenicline (NFV). NMV is produced by reaction of the amine moiety with both formaldehyde and formic acid in an Eschweiler-Clarke reaction, while NFV is formed by reaction of formic acid alone with varenicline. This represents the first report of these reactions occurring on storage of solid pharmaceutical formulations. Both formaldehyde and formic acid are formed from oxidative degradation of polyethylene glycol (PEG) used in an osmotic coating through a process heavily dependent on the physical state of the PEG. When the concentration of PEG in the coating is sufficiently low, the PEG remains phase compatible with the other component of the coating (cellulose acetate) such that its degradation (and the resulting drug reactivity) is effectively eliminated. Antioxidants in the coating and oxygen scavengers in the packaging also serve to prevent the PEG degradation, and consequently provide for drug stability.

Monitoring Dissolution Rate of Amiodarone Tablets by a Multiple Fiber-Optic Sensor System

Afiber-optic dissolution testing (FODT) system for solid pharmaceutical formulations has been constructed. The system is based on a charge-coupled device (CCD) detector and includes six fiber-optic probes. Light is produced by a small deuterium arc lamp illuminating an optical fiber bundle. Six fiber-optic dipping probes were constructed with reflection geometry. The light passes back and forth through the flow-through cuvette backed by a coated aluminum mirror. The sampling interval was typically 30 sec for all probes. The system was tested for different tablet and capsule formulations. Amiodarone is a Class III anti-arrhythmic agent. It is used for treatment of many ventricular and supraventricular arrhythmias, including arterial fibrillation. It is a highly hydrophobic drug, and factors of its formulation, including constitutional heterogeneity, surface membrane, and production technology, influence its absorption. The dissolution of marketed amiodarone tablets was tested by the system, and dissolution parameters were directly obtained from the dissolution curves. It was found that there were significant differences in the dissolution of these products.

Modelos in vitro para determinação da absorção de fármacos e previsão da relação dissolução/absorção

Fármacos contidos em formas farmacêuticas sólidas devem ter adequada solubilidade aquosa e permeabilidade intestinal para serem absorvidos após administração oral. A velocidade e a extensão com as quais um fármaco é absorvido podem variar devido às suas características físico-químicas e fatores relacionados à desintegração e dissolução. Segundo o Sistema de Classificação Biofarmacêutica (SCB), a dissolução e a permeação intestinal do fármaco podem limitar a absorção e, conseqüentemente, a ação terapêutica. Este trabalho objetiva discutir dados da literatura referentes à previsão da relação entre a dissolução de fármacos e sua absorção empregando sistemas in vitro. Para avaliar a permeação in vitro são discutidos modelos com tecidos e segmentos intestinais, vesículas extraídas de membranas e cultura de células. Na literatura existem estudos de permeabilidade utilizando células Caco-2, TC-7, 2/4/A1, MDCK e MDCK-MDR1. As células Caco-2 são extraídas de adenocarcinoma de cólon humano que, em cultura celular, se diferenciam em enterócitos, podendo ser acopladas a sistemas de dissolução. Estas técnicas representam importante ferramenta para estudos de dissolução/permeação, porém, ainda são limitadas e não conseguem reproduzir adequadamente os mecanismos de transporte ativo.

Monitoring galenical process development by near infrared chemical imaging: One case study

The objective of this study is to evaluate by NIR imaging the homogeneity of process intermediates obtained with different process parameters during the development of a new pharmaceutical solid form. The process under investigation is a solid dosage form based on extrusion. The parameters are two kinds of crystallizations, two sizes of particle of API, two screw speeds during the extrusion and two milling screens used to reduce the extrudates into a granulate form. Two kinds of intermediates are evaluated: the extrudates and the cores. Two approaches are used to analyze the data: the univariate NIR analysis which consists in wavelength selection and multivariate analysis, i.e., Classical Least Squares (CLS), which takes into account the whole spectra. The univariate method reveals good chemical homogeneity of the extrudates but differences in their physical aspect. CLS shows well-distributed excipients for all the cores; differences in the sizes of the granules have also been revealed. The univariate method can be applied on simple chemical systems such as binary mixtures. When complex samples are analyzed, multivariate analysis is the method of choice. This study demonstrates that NIR imaging can be a useful tool for the optimization of the process and for the selection of the final parameters of the process.

Physicochemical Characterization and Application of Yam (Dioscorea cayenensis‐rotundata) Starch as a Pharmaceutical Excipient

AbstractYam starch from Dioscorea cayenensis‐rotundata complex was isolated and characterized by scanning electron microscopy (SEM), particle size analysis, X‐ray diffraction, differential scanning calorimetry (DSC), compaction and rheology, and compared to maize (Zea mays) and potato (Solanum tuberosum) starches. Yam starch exhibited a log‐normal distribution of flattened ovoid shaped granules with a mean particle size of 25 µm. X‐ray diffraction showed a C‐type crystalline pattern with the degree of relative crystallinity estimated to be 34%. DSC analysis suggests that the crystalline regions in yam starch are thermally and structurally more stable as in maize and potato. Irrespective of the relative humidity (39, 67, 78% R.H.) yam starch exhibited higher moisture uptakes than maize starch and lower than potato. Intermediate values of swelling power and amylose leaching were obtained for yam as compared to maize and potato. Compaction properties of yam and potato starches were similar. However, compacts from yam presented a relatively lower tensile strength. Aqueous starch systems (4%) of yam and maize starches showed analogous shear‐thinning (pseudo‐plastic) behavior suitably described by the power‐law model. These results support the potential use of yam starch as excipient comparable to potato starch in pharmaceutical solid forms and as thickening agent similar to maize in pharmaceutical applications.

Simultaneous Determination of Caffeine, Ergotamine, and Metamizol in Solid Pharmaceutical Formulation by HPTLC-UV-FLD with Mass Confirmation by Online HPTLC-ESI-MS

A new high-throughput method is developed to quantify caffeine, ergotamine, and metamizol in a solid pharmaceutical formulation. After dissolution, the compounds are separated on silica gel 60 F(254) high-performance thin-layer chromatography (HPTLC) plates with ethyl acetate-methanol-ammonia 90:15:1 (v/v/v) as the mobile phase. Detection is performed by UV absorption at 274 nm for caffeine and metamizol, and by fluorescence at 313 /> 340 nm for ergotamine. Calibrations are linear or polynomial with determination coefficients (R(2)) >or= 0.9986. Recoveries of the three compounds are between 95% and 102% at three different concentration levels. Repeatability [relative standard deviation (RSD)] of all substances in the matrix is between +/- 0.9% and +/- 1.7%. Intermediate precision (RSD) of the three compounds range from +/- 2.0% to +/- 3.1%. Mass confirmation is performed by a single quadrupole mass spectrometry in positive electrospray ionization full scan mode for caffeine and ergotamine and in negative mode for metamizol. The results proved that this method is a simple and reliable alternative for routine analysis.

Symmetrical Derivatives of C2-Substituted Pyrrolo[2,3-f]quinolines:Synthesis, Cytotoxicity and Drug Delivery Studies

The synthesis, pharmacological properties and delivery characteristics in simulated aqueous gastric fluid of a series of symmetrical nitrogenated C2-substituted pyrrolo[2,3-f]quinolines are described. The cytotoxicity of the target molecules (5a-h) was evaluated in the human non-small lung cancer cell line NSCLCN16- L16 in vitro. One compound (5e) showed sufficient activity (IC50 = 26.4 μM) and satisfactory release characteristics from solid pharmaceutical formulations. Keywords: Symmetrical pyrrolo[2,3-f]quinolines, Synthesis, Cytotoxicity, Drug delivery

Dissolution profile evaluation of solid pharmaceutical forms containing chloramphenicol marketed in Brazil

The dissolution profile for solid pharmaceutical forms containing chloramphenicol 250 mg available in Brazil was determined using a method from the American Pharmacopoeia (United States Pharmacopoeia, 2004) and then compared. Two different methods of dissolution profile comparison were used: ANOVA, and an independent model. Differences between the formulations were reflected in the dissolution profiles. The presence of metastable polymorphs or amorphous forms of chloramphenicol palmitate might be responsible for variations in the concentration of the drug observed within formulations.

Voltammetric behavior and determination of isoniazid in pharmaceuticals by using overoxidized polypyrrole glassy carbon modified electrode

Voltammetric behavior of isoniazid (INZ) at an overoxidized polypyrrole (OPPy) modified glassy carbon electrode was investigated. The OPPy-modified glassy carbon electrode exhibited catalytic activity toward the electro-oxidation of INZ, which appeared as a reduced overpotential in a wide operational pH range of 1–13. The overall number of electrons involved in the catalytic oxidation of INZ was found 4 electrons. The diffusion coefficient of 3.6 × 10−6 cm2 s−1 for INZ was also estimated using chronoamperometry study. It has been shown that using the OPPy-modified electrode, INZ can be determined by amperometry method with limit of detection of 3.15 × 10−6 M. The method was successfully applied for analysis of INZ in solid pharmaceutical formulations. The results were favorably compared to those obtained by the reported USP method. The results of the analysis suggest that the proposed method has promise for the routine determination of INZ in the products examined.

Transfer of NIR calibrations for pharmaceutical formulations between different instruments

In order to evaluate how well existing techniques for transferring NIR calibrations perform for solid pharmaceutical formulations, a study on four assays of active ingredients was undertaken. The study included two configurations of dispersive NIR instruments and one Fourier transform (FT) instrument. Three methods for calibration transfer: slope/bias correction, local centring and piecewise direct standardisation (PDS), were tested and evaluated. Our conclusions are that the calibration transfer methods tested can perform equally well. It was shown that it is possible to transfer calibrations between instruments of different configurations or even of different types, without loosing the prediction ability of the calibration. To achieve a good calibration transfer, a larger variation in the content of the active ingredient in the samples and more samples are needed for the slope and bias correction method compared to the local centring method. For PDS to be a successful calibration transfer method, an optimisation of the number of transfer samples and how they are selected together with various factors specific for this method is needed. Local centring is the preferred transfer method as its performance is excellent yet it is simple to perform, no optimisation is needed, only a few transfer samples are required and the transfer samples do not have to vary in their content of the active ingredient.

Gastrointestinal transit and disintegration of enteric coated magnetic tablets assessed by ac biosusceptometry

The oral administration is a common route in the drug therapy and the solid pharmaceutical forms are widely used. Although much about the performance of these formulations can be learned from in vitro studies using conventional methods, evaluation in vivo is essential in product development. The knowledge of the gastrointestinal transit and how the physiological variables can interfere with the disintegration and drug absorption is a prerequisite for development of dosage forms. The aim of this work was to employing the ac biosusceptometry (ACB) to monitoring magnetic tablets in the human gastrointestinal tract and to obtain the magnetic images of the disintegration process in the colonic region. The ac biosusceptometry showed accuracy in the quantification of the gastric residence time, the intestinal transit time and the disintegration time (DT) of the magnetic formulations in the human gastrointestinal tract. Moreover, ac biosusceptometry is a non-invasive technique, radiation-free and harmless to the volunteers, as well as an important research tool in the pharmaceutical, pharmacological and physiological investigations.

Production of pregelatinised maize starch compared with maize starch as ingredient in pharmaceutical solid dose forms

Pregelatinised maize starch was prepared from evaporating to dryness 8%w/v of maize starch mucilage and pulverising it. Its physicochemical properties were compared with maize starch powder. Its higher and tapped densities resulted in lower Carr's index. Its higher particle flow rate lower angle of reponse could render it a better candidate in capsule filling and tablet compression. The later properties could allow more uniform dose distribution by weight and lower power consumption for compression. Its higher intraparticulate porosity and more amorphous disruption by the gelatinisation could cause dose form faster disentegration and therefore enhanced faster dissolution for faster drug bioavailability. Key words: Pregelatinised starch; Maize starch; Physicochemical properties, Comparative pharmaceutical excipient. Nig. J. Pharm. Res. 3(1) 2004: 66-71

Sensitive sequential injection determination of naproxen based on interaction with β-cyclodextrin

A sensitive sequential injection analysis (SIA) methodology for the fluorimetric determination of naproxen is proposed. The developed automatic analytical procedure is based on the complexation of naproxen with β-cyclodextrin (β-CD) yielding an enhanced fluorimetric signal ( λ ex = 280 nm, λ em = 356 nm). Linear calibration plots were obtained for naproxen concentrations up to 1 × 10 −5 mol l −1. The developed methodology exhibited a good precision, with a R.S.D. < 2.1% ( n = 15). The detection limit of the determination was 1.9 × 10 −7 mol l −1 with a sampling rate of about 70 h −1. The automatic method was applied to the determination of naproxen in pharmaceutical formulations. The obtained results were compared with those furnished by the reference procedure and the relative deviations were lower than 3.6%. No interference was found from the excipients usually used in solid pharmaceutical formulations.

Characterizing process effects on pharmaceutical solid forms using near-infrared spectroscopy and infrared imaging

Near-infrared spectroscopy (NIRS) has become a widely used analytical technique in the pharmaceutical industry, serving for example to determine the active substance or water content of tablets. Its great advantage lies in the minimal sample preparation required and speed of measurement. In a study designed to detect the effects of process on tablet dissolution, we describe the application of NIRS to the detection and identification of changes in uncoated and coated tablets in response to pilot-scale changes in process parameters during melt granulation, compression, and coating. Beginning with a qualitative comparison between pharmaceutical batches, we show that NIRS and principal component analysis can separate batches produced with different melt granulation parameters and differentiate between cores compressed with different compaction forces. Complementary infrared imaging can also explain the difference in dissolution properties between samples produced with different melt granulation parameters. NIRS is sensitive to changes in coating formulation, the quality of a coating excipient (hydroxypropyl methylcellulose), and coating time. In a concluding quantitative analysis, we demonstrate the feasibility of NIRS in a manufacturing context for predicting coating time and detecting production cores failing to meet dissolution test specifications.