Understanding the solid forms of 5E-phenylethenylbenzofuroxan with different in vivo anti-T. cruzi activity

5E-Phenylethenylbenzofuroxan (5PhEBfx) was reported as an excellent anti-Chagas drug candidate. However, its oral bioavailability was affected by the crystallization process. Two samples exhibiting variable in vivo activity was investigated: a thin yellow powder (5PhEBfx-Y) and orange needles (5PhEBfx-O). X-ray powder diffraction, differential scanning calorimetry, vibrational spectroscopy, optical and electron scanning microscopies were applied to investigate both solid forms in order to correlate the solid-state properties with the variable bioavailability of 5PhEBfx. It was observed that 5PhEBfx-Y have a better solubility and consequently higher bioavailability when compared with 5PhEBfx-O. This result suggests that the difference of activity between these two 5E-Phenylethenylbenzofuroxanes could be associated with the solid forms, which also cause the coloration variation.

Solid oral forms availability in children:a cost saving investigation

AIM: To assess the suitability and potential cost savings, from both the hospital and community perspective, of prescribed oral liquid medicine substitution with acceptable solid forms for children over 2 years. METHOD: Oral liquid medicines dispensed from a paediatric hospital (UK) in 1 week were assessed by screening for existence of the solid form alternative and evaluating the acceptability of the available solid form, firstly related to the prescribed dose and secondly to acceptable size depending on the child's age. Costs were calculated based on providing treatment for 28 days or prescribed duration for short term treatments. RESULTS: Over 90% (440/476) of liquid formulations were available as a marketed solid form. Considering dosage acceptability (maximum of 10% deviation from prescribed dosage or 0% for narrow therapeutic range drugs, maximum tablet divisions into quarters) 80% of liquids could be substituted with a solid form. The main limitation for liquid substitution would be solid form size. However, two-thirds of prescribed liquids could have been substituted with a suitable solid form for dosage and size, with estimated savings being of 5K and 8K in 1 week, respectively based on hospital and community costs, corresponding to a projected annual saving of 238K and 410K (single institution). CONCLUSION: Whilst not all children over 2 years will be able to swallow tablets, drug cost savings if oral liquid formulations were substituted with suitable solid dosage forms would be considerable. Given the numerous advantages of solid forms compared with liquids, this study may provide a theoretical basis for investing in supporting children to swallow tablets/capsules.

Design And Synthesis Of N-acylated Aza-goniothalamin Derivatives And Evaluation Of Their In Vitro And In Vivo Antitumor Activity.

Herein we describe the synthesis of a focused library of compounds based on the structure of goniothalamin (1) and the evaluation of the potential antitumor activity of the compounds. N-Acylation of aza-goniothalamin (2) restored the in vitro antiproliferative activity of this family of compounds. 1-(E)-But-2-enoyl-6-styryl-5,6-dihydropyridin-2(1H)-one (18) displayed enhanced antiproliferative activity. Both goniothalamin (1) and derivative 18 led to reactive oxygen species generation in PC-3 cells, which was probably a signal for caspase-dependent apoptosis. Treatment with derivative 18 promoted Annexin V/7-aminoactinomycin D double staining, which indicated apoptosis, and also led to G2 /M cell-cycle arrest. In vivo studies in Ehrlich ascitic and solid tumor models confirmed the antitumor activity of goniothalamin (1), without signs of toxicity. However, derivative 18 exhibited an unexpectedly lower in vivo antitumor activity, despite the treatments being administered at the same site of inoculation. Contrary to its in vitro profile, aza-goniothalamin (2) inhibited Ehrlich tumor growth, both on the ascitic and solid forms. Our findings highlight the importance of in vivo studies in the search for new candidates for cancer treatment.

Nuclear Quadrupole Resonance: A Technique to Control Hydration Processes in the Pharmaceutical Industry

Pharmaceuticals can exist in many solid forms, which can have different physical and chemical properties. These solid forms include polymorphs, solvates, amorphous, and hydrates. Particularly, hydration process can be quite common since pharmaceutical solids can be in contact with water during manufacturing process and can also be exposed to water during storage. In the present work, it is proved that NQR technique is capable of detecting different hydrated forms not only in the pure raw material but also in the final product (tablets), being in this way a useful technique for quality control. This technique was also used to study the dehydration process from pentahydrate to trihydrate.

Detection, Determination of Chemical Composition and Chemical Profiling of Counterfeit Medicines by Raman Spectroscopy.

Raman spectroscopy has become a widespread technique for the analysis ofpharmaceutical solid forms. The application proposed here is the investigationof counterfeit medicines. This serious global issue requires quick and accurateidentification methods to fight against this phenomenon. Thanks to its chemicalselectivity, rapidity of analysis and potential of generating repeatable spectralprofiles, Raman spectroscopy presents distinct advantages for the analysis ofcounterfeits. Combined with chemometric tools, the technique enablesthe detection, the determination of chemical composition and the profiling ofmedicine counterfeits.

Detection and chemical profiling of medicine counterfeits by Raman spectroscopy and chemometrics

Raman spectroscopy combined with chemometrics has recently become a widespread technique for the analysis of pharmaceutical solid forms. The application presented in this paper is the investigation of counterfeit medicines. This increasingly serious issue involves networks that are an integral part of industrialized organized crime. Efficient analytical tools are consequently required to fight against it. Quick and reliable authentication means are needed to allow the deployment of measures from the company and the authorities. For this purpose a method in two steps has been implemented here. The first step enables the identification of pharmaceutical tablets and capsules and the detection of their counterfeits. A nonlinear classification method, the Support Vector Machines (SVM), is computed together with a correlation with the database and the detection of Active Pharmaceutical Ingredient (API) peaks in the suspect product. If a counterfeit is detected, the second step allows its chemical profiling among former counterfeits in a forensic intelligence perspective. For this second step a classification based on Principal Component Analysis (PCA) and correlation distance measurements is applied to the Raman spectra of the counterfeits.

Conformational polymorphism of the antidiabetic drug chlorpropamide

In this paper, the main features of Raman spectroscopy, one of the first choice methods in the study of polymorphism in pharmaceuticals, are presented taking chlorpropamide as a case of study. The antidiabetic drug chlorpropamide (1-[4-chlorobenzenesulphonyl]-3-propyl urea), which belongs to the sulfonylurea class, is known to exhibit, at least, six polymorphic phases. These forms are characterized not only by variations in their molecular packing but also in their molecular conformation. In this study, the polymorphism of chlorpropamide is discussed on the basis of Raman scattering measurements and quantum mechanical calculations. The main spectroscopic features that fingerprint the crystalline forms are correlated with the corresponding crystalline structures. Using a theoretical approach on the energy dependence of the conformers, simulated molecular torsion angles are plotted versus the formation energy, which provides a satisfactory agreement between the torsion angles at the energy minima and the experimental values observed in the different solid forms of chlorpropamide. Copyright (C) 2011 John Wiley & Sons, Ltd.

Economic Talc Deposits of Montana and Related Firing Problems

This thesis has to do with a study of the produc­tion of talc in Montana, describing the local geology of each deposit, and a description of the laboratory tests that were made on various grades of Montana talc in an attempt to determine why some grades of talc can be burned in solid forms while others must be ground, mixed with a binder and molded.

New insights on the crystalline forms in binary systems of n-alkanes: Characterization of the solid ordered phases in the phase diagram tricosane + pentacosane

X-ray diffraction analyses of the pure components n-tricosane and n-pentacosane and of their binary mixed samples have enabled us to characterize the crystalline phases observed at low temperature. On the contrary to what was announced in literature on the structural behavior of mixed samples in odd-odd binary systems with D n = 2, the three domains are not all orthorhombic. This work has enabled us to show that two of the domains are, in fact, monoclinic, (Aa, Z = 4) and the other one is orthorhombic (Pca21, Z = 4). The conclusions drawn in this work can be easily transposed to other binary systems of n-alkanes.

Prevalence of patients' difficulties in swallowing solid oral dosage forms

Introduction Swallowing difficulties, or dysphagia, can occur in anyage group, although it is most common among elderly people. It canaffect patients' ability to take solid oral dosage forms, thus compromisingmedication adherence. Although literature is poor, availabledata show that prevalence in the general population ranges from 25 to60%. Prevalence in community pharmacies needs to be explored.Materials & Methods Community pharmacies were recruited from arandom selection in three Swiss states: Basel-Stadt (BS), Basel-Landschaft (BL) and Lausanne (LA). Patients' ability to swallowsolid oral medications was enquired with a semi-structured interview;the interviewer spent 4 h in each included pharmacy. Each consecutivepatient (18 years and older) entering the pharmacy with aprescription for at least 3 different solid oral forms was enrolled.Study was approved by the Lausanne ethics committee.Results Sixty pharmacies took part in the study (20 in BS, 10 in BL,30 in LA) between March and May 2010. Patient inclusion rate was77.8% (410/527). Prevalence of swallowing disorders was 22.4% (92/410). Patients with swallowing disorders were older (mean age: 67.5± 16 years vs. 63.0 ± 14 years, range 19-96; p = 0.03) and moreoften women (69.6% vs. 59.1%; Chi2 = 3.3, p = 0.04) than patientswithout swallowing disorders. They had on average 4.6 ± 2.7 drugswith a mean number of 5.5 ± 3.3 tablets or capsules to take daily,which didn't differ from the number of drugs taken by patientswithout swallowing difficulties (4.9 ± 2.5 drugs and 5.9 ± 3.5 tablets;n.s.). The difficulty was mainly related to the big size (63%) orthe quality of pill coating (rough, sticky, 14%). Twenty-one patients(37.5%) stated that their swallowing disorders resulted in nonadherence, rated as rarely (12 patients), sometimes (6 patients), veryoften (1 patient) or always (2 patients). According to patients, nopharmacist and only 2 physicians enquired about patients' swallowingissue.Discussion & Conclusion Swallowing difficulties are frequent amongpatients in community pharmacies in Switzerland with an estimatedprevalence of 22%. The problem resulted in non adherence or partialadherence in at least 35% of these patients. However, pharmacists andphysicians did not routinely inquire about the disorder. Guidelinesshould be developed for promoting systematic approaches of patientsin community pharmacies.

Porosity measurement of solid pharmaceutical dosage forms by gamma-ray transmission

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Non-conventional applications of computerized tomography: Analysis of solid dosage forms produced by pharmaceutical industry

X-ray computed tomography (CT) refers to the cross-sectional imaging of an object measuring the transmitted radiation at different directions. In this work, we describe a non-conventional application of computerized tomography: visualization and improvements in the understanding of some internal structural features of solid dosage forms. A micro-CT X-ray scanner, with a minimum resolution of 30 μm was used to characterize some pharmaceutical tablets, granules, controlled-release osmotic tablet and liquid-filled soft-gelatin capsules. The analysis presented in this work are essentially qualitative, but quantitative parameters, such as porosity, density distribution, tablets dimensions, etc. could also be obtained using the related CT techniques. © 2010 American Institute of Physics.

Biowaiver monographs for immediate-release solid oral dosage forms: Stavudine

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing stavudine (d4T) are reviewed. According to Biopharmaceutics Classification System (BCS), d4T can be assigned to BCS class I. No problems with BE of IR d4T formulations containing different excipients and produced by different manufacturing methods have been reported and, hence, the risk of bioinequivalence caused by these factors appears to be low. Furthermore, d4T has a wide therapeutic index. It is concluded that a biowaiver is appropriate for IR solid oral dosage forms containing d4T as the single active pharmaceutical ingredient (API) provided that (a) the test product contains only excipients present in the IR d4T drug products that have been approved in a number of countries for the same dosage form, and (b) both test product and its comparator are either very rapidly dissolving or rapidly dissolving with similarity of dissolution profiles demonstrated at pH 1.2, 4.5, and 6.8. (c) 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:1016, 2012

Solubility and permeability as in vitro predictors for in vivo performance of fenofibrate IR solid dosage forms

This current work focused on the simulation of in vivo dissolution and permeation in order to be able to predict the in vivo performance of orally administered fenofibrate immediate release formulations. Therefore, the effects of the formulation surfactants on in vivo solubility and permeation of fenofibrate under physiologically relevant excipient concentrations were emphasized.rnIt was shown that the surfactant sodium dodecyl sulfate (SDS) may decrease rather than increase the solubility of fenofibrate in vivo. This was related to the interference of SDS with the vesicular system of the biorelevant medium, FaSSIFmod, and therefore its solubilization capacity. rnMoreover, in vitro permeation studies revealed that SDS concentrations inversely correlated with fenofibrate permeability. Through combination of the observed permeation and solubility data a good in vitro/in vivo correlation regarding Cmax values in humans could be established for five fenofibrate formulations which were based on the same manufacturing technique.rnBesides the experimental part, the major characteristics and their potential implementation in a dissolution/permeation device were discussed based on the promising realization of the in vitro solubility and permeation methods. rn