Short cycle times for cost-efficient processing in lyophilized formulations

Pharmaceutical scientists who bulk freeze dry need to foremost identify what quality factors are of a priority during cycle development since the economics of freeze-drying do not allow for both the cost-efficient production and the ability to obtain the highest quality score across all quality factors. Consider; morphology, activity, dissolution, long-term storage, packaging and cost.

Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Feasibility Studies and Physicochemical Characterisation

Engineered cocrystals offer an alternative solid drug form with tailored physicochemical properties. Interestingly, although cocrystals provide many new possibilities, they also present new challenges, particularly in regard to their design and large-scale manufacture. Current literature has primarily focused on the preparation and characterization of novel cocrystals typically containing only the drug and coformer, leaving the subsequent formulation less explored. In this paper we propose, for the first time, the use of hot melt extrusion for the mechanochemical synthesis of pharmaceutical cocrystals in the presence of a meltable binder. In this approach, we examine excipients that are amenable to hot melt extrusion, forming a suspension of cocrystal particulates embedded in a pharmaceutical matrix. Using ibuprofen and isonicotinamide as a model cocrystal reagent pair, formulations extruded with a small molecular matrix carrier (xylitol) were examined to be intimate mixtures wherein the newly formed cocrystal particulates were physically suspended in a matrix. With respect to formulations extruded using polymeric carriers (Soluplus and Eudragit EPO, respectively), however, there was no evidence within PXRD patterns of either crystalline ibuprofen or the cocrystal. Importantly, it was established in this study that an appropriate carrier for a cocrystal reagent pair during HME processing should satisfy certain criteria including limited interaction with parent reagents and cocrystal product, processing temperature sufficiently lower than the onset of cocrystal Tm, low melt viscosity, and rapid solidification upon cooling.

Peptide Therapeutics and the Pharmaceutical Industry: Barriers Encountered Translating from the Laboratory to Patients

Peptides are receiving increasing interest as clinical therapeutics. These highly tunable molecules can be tailored to biocompatibility and biodegradability with simultaneously selective and potent therapeutic effects. Despite challenges regarding up-scaling and licensing of peptide products, their vast clinical potential is reflected in the 60 plus peptide-based therapeutics already on the market, and the further 500 derivatives currently in developmental stages. Peptides are proving effective for a multitude of disease states including: type 2 diabetes (controlled using the licensed glucagon-like peptide-1 receptor liraglutide); irritable bowel syndrome managed with linaclotide (currently at approval stages); acromegaly (treated with octapeptide somostatin analogues lanreotide and octreotide); selective or broad spectrum microbicidal agents such as the Gram-positive selective PTP-7 and antifungal heliomicin; anticancer agents including goserelin used as either adjuvant or for prostate and breast cancer,and the first marketed peptide derived vaccine against prostate cancer, sipuleucel-T. Research is also focusing on improving the biostability of peptides. This is achieved through a number of mechanisms ranging from replacement of naturally occurring L-amino acid enantiomers with D-amino acid forms, lipidation, peptidomimetics, N-methylation, cyclization and exploitation of carrier systems. The development of self-assembling peptides are paving the way for sustained release peptide formulations and already two such licensed examples exist, lanreotide and octreotide. The versatility and tunability of peptide-based products is resulting in increased translation of peptide therapies, however significant challenges remain with regard to their wider implementation. This review highlights some of the notable peptide therapeutics discovered to date and the difficulties encountered by the pharmaceutica lindustry in translating these molecules to the clinical setting for patient benefit, providing some possible solutions to the most challenging barriers. 

Study Of The Homogeneity Of Drug Loaded In Polymeric Films Using Near-infrared Chemical Imaging And Split-plot Design.

Split-plot design (SPD) and near-infrared chemical imaging were used to study the homogeneity of the drug paracetamol loaded in films and prepared from mixtures of the biocompatible polymers hydroxypropyl methylcellulose, polyvinylpyrrolidone, and polyethyleneglycol. The study was split into two parts: a partial least-squares (PLS) model was developed for a pixel-to-pixel quantification of the drug loaded into films. Afterwards, a SPD was developed to study the influence of the polymeric composition of films and the two process conditions related to their preparation (percentage of the drug in the formulations and curing temperature) on the homogeneity of the drug dispersed in the polymeric matrix. Chemical images of each formulation of the SPD were obtained by pixel-to-pixel predictions of the drug using the PLS model of the first part, and macropixel analyses were performed for each image to obtain the y-responses (homogeneity parameter). The design was modeled using PLS regression, allowing only the most relevant factors to remain in the final model. The interpretation of the SPD was enhanced by utilizing the orthogonal PLS algorithm, where the y-orthogonal variations in the design were separated from the y-correlated variation.

Determination Of Tetrakis(hydroxymethyl)phosphonium Sulfate In Commercial Formulations And Cooling Water By Capillary Electrophoresis With Contactless Conductivity Detection.

A novel capillary electrophoresis method using capacitively coupled contactless conductivity detection is proposed for the determination of the biocide tetrakis(hydroxymethyl)phosphonium sulfate. The feasibility of the electrophoretic separation of this biocide was attributed to the formation of an anionic complex between the biocide and borate ions in the background electrolyte. Evidence of this complex formation was provided by (11) B NMR spectroscopy. A linear relationship (R(2) = 0.9990) between the peak area of the complex and the biocide concentration (50-900 μmol/L) was found. The limit of detection and limit of quantification were 15.0 and 50.1 μmol/L, respectively. The proposed method was applied to the determination of tetrakis(hydroxymethyl)phosphonium sulfate in commercial formulations, and the results were in good agreement with those obtained by the standard iodometric titration method. The method was also evaluated for the analysis of tap water and cooling water samples treated with the biocide. The results of the recovery tests at three concentration levels (300, 400, and 600 μmol/L) varied from 75 to 99%, with a relative standard deviation no higher than 9%.

Tecnologia de nanocristais em fármacos

The use of poorly water soluble molecules in pharmaceutical area has grown. Since these molecules exhibit low oral bioavailability, they are not used in intravenous administrations. Therefore, it is necessary to develop their new formulations with the aim to increase their oral bioavailabilities as to enable intravenous applications. One of the few possibilities in achieving this is a nanonization process that can produce crystals smaller than 1 μm by high pressure homogenization and without use of organic solvents. This mini-review describes technical aspects of the nanocrystal production, morphological aspects (polymorphisms), the market relevance of the nanocrystals products that are already in clinical phase or at the market, as well as, perspectives for the near future.

Flow injection green method for the quantitative analysis of ketoconazole in pharmaceutical preparations

A flow injection method for the quantitative analysis of ketoconazole in tablets, based on the reaction with iron (III) ions, is presented. Ketoconazole forms a red complex with iron ions in an acid medium, with maximum absorbance at 495 nm. The detection limit was estimated to be 1×10--4 mol L-1; the quantitation limit is about 3×10--4 mol L-1 and approximately 30 determinations can be performed in an hour. The results were compared with those obtained with a reference HPLC method. Statistical comparisons were done using the Student's t procedure and the F test. Complete agreement was found at the 0.95 significance level between the proposed flow injection and the HPLC procedures. The two methods present similar precision, i.e., for HPLC the mean relative standard deviation was ca. 1.2% and for FIA ca. 1.6%.

Desenvolvimento, produção e caracterização de nanocristais de fármacos pouco solúveis

Poorly soluble drugs have low bioavailability, representing a major challenge for the pharmaceutical industry. Processing drugs into the nanosized range changes their physical properties, and these are being used in pharmaceutics to develop innovative formulations known as Nanocrystals. Use of nanocrystals to overcome the problem of low bioavailability, and their production using different techniques such as microfluidization or high pressure homogenization, was reviewed in this paper. Examples of drugs, cosmetics and nutraceutical ingredients were also discussed. These technologies are well established in the pharmaceutical industry and are approved by the Food and Drug Administration.

The use of a graphite-silicone rubber composite electrode in the determination of rutin in pharmaceutical formulation

The possibility of using a graphite silicone-rubber composite electrode (GSR) in a differential pulse voltammetric(DPV) procedure for rutin (vitamin P) determination is described. Cyclic voltammograms of rutin presented a reversible pair of oxidation/reduction peaks respectively at 0.411 and 0.390 V (vs. SCE) at the GSR surface in Britton-Robinson(B-R) buffer solution pH 4.0. In DPV after optimization of conditions, an oxidation peak at 0.370 V (vs. SCE) was used to quantitative determination of rutin in B-R buffer solution pH 4.0. In this case a linear dynamic range of 5.0×10-8 to 50.0×10-8 mol L-1 was observed with a detection limit of 1.8×10-8 mol L-1 for the analyte. Recoveries from 94 to 113% were observed. The electrode surface was renewed by polishing after each determination, with a repeatability of 1.09 ± 0.06 µA (n = 10) peak current. Rutin was determined in a pharmaceutical formulation using the proposed electrode and the results agreed with those from an official method within 95% confidence level.

Potentiometric determination of Minoxidil in topical use pharmaceutical samples

A potentiometric titration method for the determination of minoxidil based on its redox reaction with K2Cr2O7 is described. The best results were observed using 1.00 x 10-3 mol L-1 K2Cr2O7 and 1.00 x 10-2 mol L-1 minoxidil solutions, and the minoxidil as titrant in 2.00 mol L-1 H2SO4 medium. The method was applied to commercial samples and compared with the results from a chromatographic procedure. Recoveries from 97.4 to 98.7 % were observed depending on the sample. Comparison with the chromatographic procedure reveled agreement within 90% confidence level.

Brazilian scientific production on pharmaceutical care from 1990 to 2009

Brazilian scientific production on pharmaceutical care was identified based on articles indexed on the Medline, Embase, Lilacs, Web of Science and International Pharmaceutical Abstracts databases. Sixty-three articles published in both national and international journals were retrieved. With regard to authors, 72.3% were from the Southeast and South Regions, and 60.8% were affiliated to public universities. In relation to the type of studies, 85.7% were descriptive, and the most frequently researched fields were community pharmacies, hospitals and primary health care units. Articles were original in 65.1% of cases, updates in 20.6%, and reviews in 7.9%. An increase in publications commenced in 2006. In 31.7% of cases, authors had adopted a bibliographical study design, 28.6% qualitative study, 23.8% intervention, and 15.9% observational study design. The most researched subjects were elderly with chronic diseases. The importance of stimulating the conducting of experimental and qualitative studies, as well as amplifying authorship affiliated with the service area, foreign authors and with research in a wide variety of practice settings were highlighted. Despite the limited quantity of articles, an increase in their number as well as in their scope and quality is expected, so as to create further knowledge that contributes to the recognition of pharmacists' actions by patient healthcare teams.

Evaluation of laser induced breakdown spectrometry for the determination of macro and micronutrients in pharmaceutical tablets

The aim of this work is to demonstrate the feasibility of laser induced breakdown spectrometry (LIBS) for the determination of macro and micronutrients in multielement tablets. The experimental setup was designed by using a laser Q-switch (Nd:YAG, 10 Hz, lambda = 1064 nm) and the emission signals were collected by lenses into an optical fiber coupled to an echelle spectrometer equipped with a high-resolution intensified charge coupled device (ICCD). Tablets were cryogenically ground and thereafter pelletized before LIBS analysis. Calibration curves were made by employing samples and mixtures of commercial multielement tablets with binders at different ratios. Best results were achieved by using the following experimental conditions: 29 J cm(-2) laser fluence, 165 mm lens to sample distance (f = 200 mm), 2.0 mu s delay time, 5.0 mu s integration time and 5 accumulated laser pulses. In general, the results obtained by the proposed LIBS procedure were in agreement with those obtained by ICP OES from the corresponding acid digests and coefficients variation of LIBS measurements varied from 2 to 16%. The metrological figures of merit indicate that LIBS fits for the intended purposes, and can be recommended for the analysis of multielement tablets and similar matrices aiming the determination of Ca, Cu, Fe, Mg, Mn, P and Zn.

A STUDY OF PENALTY FORMULATIONS USED IN THE NUMERICAL APPROXIMATION OF A RADIALLY SYMMETRIC ELASTICITY PROBLEM

We consider a class of two-dimensional problems in classical linear elasticity for which material overlapping occurs in the absence of singularities. Of course, material overlapping is not physically realistic, and one possible way to prevent it uses a constrained minimization theory. In this theory, a minimization problem consists of minimizing the total potential energy of a linear elastic body subject to the constraint that the deformation field must be locally invertible. Here, we use an interior and an exterior penalty formulation of the minimization problem together with both a standard finite element method and classical nonlinear programming techniques to compute the minimizers. We compare both formulations by solving a plane problem numerically in the context of the constrained minimization theory. The problem has a closed-form solution, which is used to validate the numerical results. This solution is regular everywhere, including the boundary. In particular, we show numerical results which indicate that, for a fixed finite element mesh, the sequences of numerical solutions obtained with both the interior and the exterior penalty formulations converge to the same limit function as the penalization is enforced. This limit function yields an approximate deformation field to the plane problem that is locally invertible at all points in the domain. As the mesh is refined, this field converges to the exact solution of the plane problem.

Biodeterioration of painted mortar surfaces in tropical urban and coastal situations: Comparison of four paint formulations

Four different architectural acrylic paint formulations were tested by exposure to weathering for 7 years in the urban site of Sao Paulo and the coastal site of Ubatuba, South-East Brazil. Surface discolorations and detachment of coatings were assessed and the components of the biofilms were identified by standard microbiological methods. The painted surfaces of the mortar panels were much more discolored in Ubatuba, where major components of the biofilms were the cyanobacteria Gloeocapsa and Scytonema. In two of the four paint films, a pink coloration on the surface at this coastal site, caused mainly by red-pigmented Gloeocapsa, produced high discoloration ratings, but low degradation (as measured by detachment). Biofilms in Sao Paulo contained the same range of phototrophs, but in lesser quantity. However, fungal numbers, as determined by plating, were higher. Detachment ratings in this urban site were only slightly lower than in Ubatuba. The matt paint performed worst of the four, with silk and semi-gloss finishes giving lowest biodeterioration ratings. The matt elastomeric paint performed well at both sites, apart from becoming almost 100% covered by the pink biofilm in Ubatuba. Unpainted mortar panels became intensely discolored with a black biofilm, showing that all the paints had achieved one of their objectives, that of surface protection of the substrate. The value of PVC (pigment volume content) as an indicator of coatings biosusceptibility, is questioned. (C) 2011 Elsevier Ltd. All rights reserved.