Investigating physical properties of solid dosage forms during pharmaceutical processing : Process analytical applications of vibrational spectroscopy

In order to improve and continuously develop the quality of pharmaceutical products, the process analytical technology (PAT) framework has been adopted by the US Food and Drug Administration. One of the aims of PAT is to identify critical process parameters and their effect on the quality of the final product. Real time analysis of the process data enables better control of the processes to obtain a high quality product. The main purpose of this work was to monitor crucial pharmaceutical unit operations (from blending to coating) and to examine the effect of processing on solid-state transformations and physical properties. The tools used were near-infrared (NIR) and Raman spectroscopy combined with multivariate data analysis, as well as X-ray powder diffraction (XRPD) and terahertz pulsed imaging (TPI). To detect process-induced transformations in active pharmaceutical ingredients (APIs), samples were taken after blending, granulation, extrusion, spheronisation, and drying. These samples were monitored by XRPD, Raman, and NIR spectroscopy showing hydrate formation in the case of theophylline and nitrofurantoin. For erythromycin dihydrate formation of the isomorphic dehydrate was critical. Thus, the main focus was on the drying process. NIR spectroscopy was applied in-line during a fluid-bed drying process. Multivariate data analysis (principal component analysis) enabled detection of the dehydrate formation at temperatures above 45°C. Furthermore, a small-scale rotating plate device was tested to provide an insight into film coating. The process was monitored using NIR spectroscopy. A calibration model, using partial least squares regression, was set up and applied to data obtained by in-line NIR measurements of a coating drum process. The predicted coating thickness agreed with the measured coating thickness. For investigating the quality of film coatings TPI was used to create a 3-D image of a coated tablet. With this technique it was possible to determine coating layer thickness, distribution, reproducibility, and uniformity. In addition, it was possible to localise defects of either the coating or the tablet. It can be concluded from this work that the applied techniques increased the understanding of physico-chemical properties of drugs and drug products during and after processing. They additionally provided useful information to improve and verify the quality of pharmaceutical dosage forms

Preserving patent policy space and securing access to medicines in developing countries: the role of states and pharmaceutical corporations

This thesis examines the tension between patent rights and the right to health and it recognizes patent rights on pharmaceutical products as one of the factors responsible for the problem of lack of access to affordable medicines in developing countries. The thesis contends that, in order to preserve their patent policy space and secure access to affordable medicines for their citizens, developing countries should incorporate a model of human rights into the design, implementation, interpretation, and enforcement of their national patent laws. The thesis provides a systematic analysis of court decisions from four key developing countries (Brazil, India, Kenya, and South Africa) and it assesses how the national courts in these countries resolve the tension between patent rights and the right to health. Essentially, this thesis demonstrates how a model of human rights can be incorporated into the adjudication of disputes involving patent rights in national courts. Focusing specifically on Brazil, the thesis equally demonstrates how policy makers and law makers at the national level can incorporate a model of human rights into the design or amendment of their national patent law. This thesis also contributes to the ongoing debate in the field of business and human rights with regard to the mechanisms that can be used to hold corporate actors accountable for their human rights responsibilities. This thesis recognizes that, while states bear the primary responsibility to respect, protect, and fulfil the right to health, corporate actors such as pharmaceutical companies also have a baseline responsibility to respect the right to health. This thesis therefore contends that pharmaceutical companies that own patent rights on pharmaceutical products can be held accountable for their right to health responsibilities at the national level through the incorporation of a model of civic participation into a country’s patent law system.

On international cost-sharing of pharmaceutical R&D

Ramsey pricing has been proposed in the pharmaceutical industry as a principle to price discriminate among markets while allowing to recover the (fixed) R&D cost. However, such analyses neglect the presence of insurance or the fund raising costs for most of drug reimbursement. By incorporating these new elements, we aim at providing some building blocks towards an economic theory incorporating Ramsey pricing and insurance coverage. We show how coinsurance affects the optimal prices to pay for the R&D investment. We also show that under certain conditions, there is no strategic incentive by governments to set coinsurance rates in order to shift the financial burden of R&D. This will have important implications to the application of Ramsey pricing principles to pharmaceutical products across countries.

Pharmaceutical patent bargains: the Brazilian experience

In the backdrop of the strict patent regime flatly adopted by the World Trade Organization (WTO) for all countries, a few countries constantly challenge this system through aggressive patent bargains. Within the pharmaceutical sector, noticeably, some countries now threaten to issue or otherwise actually issue compulsory licenses that may sway large pharmaceutical companies into selling drugs with large discounts or into granting voluntary licenses domestically. That is conspicuously the negotiation strategy adopted by Brazil in its negotiations with big international pharmaceutical companies.This paper explains Brazil’s aggressive bargaining approach based on an analysis of two aspects of its political economy. The first has to do with the international context of patent bargaining in the post-WTO era. Accordingly, the existence of large and fast growing domestic markets position countries such as Brazil as strategic destinations for Foreign Direct Investment (FDI) and trade. Together with an absence of a propensity to innovate in pharmaceutical products, these conditions boost Brazil’s bargaining power for issuing compulsory licenses over pharmaceutical products. The second aspect is related to political economy dynamics inside Brazil. Accordingly, the political framework in Brazil undermines long-term policies and favors short-sighted ones also vis-a-vis R&D investments in the pharmaceutical industry. This remains true regardless of the strictness of the patent regime in place. The lesson of Brazil is relevant arguably for other more powerful developing countries which presently examine Brazil's approach while further challenging the WTO's strict patent policy for the future.

Spectrophotometric determination of dipyrone in pharmaceutical preparations by using chromotropic acid

A spectrophotometric method for the determination of dipyrone in pharmaceutical preparations is proposed. This method is based on selective oxidation of dipyrone, in the presence of sulphuric acid, splitting off formaldehyde which reacts with chromotropic acid, also in a sulphuric acid medium, producing a violet-red compound (lambda(max) 575 nm). Beer's law is obeyed in a concentration range of 0.57-5.7 ppm dipyrone with an excellent correlation coefficient (r = 0.9997). The results show a simple, accurate, selective and readily applied method to the determination of dipyrone in pharmaceutical products. The analytical results obtained for these products by the proposed method are in agreement with those of the Brazilian Pharmacopoeia procedure. No interference was observed from common excipients in formulations. Recoveries were within 98.7-101.2%, with standard deviations ranging from 0.2 to 1.7%. (C) 1999 Elsevier B.V. S.A. All rights reserved.

Spectrophotometric determination of methyldopa in pharmaceutical formulations

A new, simple, precise, rapid and low-cost spectrophotometric method for methyldopa determination in pharmaceutical preparations is described. This method is based on the complexation reaction of methyldopa with molybdate. Absorbance of the resulting yellow coloured product is measured at 410 nm. Beer's Law is obeyed in a concentration range of 50 - 200 μg ml -1 methyldopa with an excellent correlation coefficient (r = 0.9999). No interference was observed from common excipients in formulations. The results show a simple, accurate, fast and readily applied method to the determination of methyldopa in pharmaceutical products. The analytical results obtained for these products by the proposed method are in agreement with those of the Brazilian Pharmacopoeia procedure at 95% confidence level.

Recent applications of analytical techniques for quantitative pharmaceutical analysis: A review

The intension of this paper was to review and discuss some of the current quantitative analytical procedures which are used for quality control of pharmaceutical products. The selected papers were organized according to the analytical technique employed. Several techniques like ultraviolet/visible spectrophotometry, fluorimetry, titrimetry, electroanalytical techniques, chromatographic methods (thin-layer chromatography, gas chromatography and high-performance liquid chromatography), capillary electrophoresis and vibrational spectroscopies are the main techniques that have been used for the quantitative analysis of pharmaceutical compounds. In conclusion, although simple techniques such as UV/VIS spectrophotometry and TLC are still extensively employed, HPLC is the most popular instrumental technique used for the analysis of pharmaceuticals. Besides, a review of recent works in the area of pharmaceutical analysis showed a trend in the application of techniques increasingly rapid such as ultra performance liquid chromatography and the use of sensitive and specific detectors as mass spectrometers.

Internal standard for amorphous pharmaceuticals products quantification and an application of Parametric Rietveld refinement using time, temperature and relative humidity as 'non-crystallographic' parameters

Pós-graduação em Química - IQ

Quantification of terbinafine in pharmaceutical tablets using capillary electrophoresis with contactless conductivity detection and batch injection analysis with amperometric detection

Terbinafine hydrochloride (TerbHCl) is an allylamine derivative with fungicidal action, especially against dermatophytes. Different analytical methods have been reported for quantifying TerbHCl in different samples. These procedures require time-consuming sample preparation or expensive instrumentation. In this paper, electrochemical methods involving capillary electrophoresis with contactless conductivity detection, and amperometry associated with batch injection analysis, are described for the determination of TerbHCl in pharmaceutical products. In the capillary electrophoresis experiments, terbinafine was protonated and analyzed in the cationic form in less than 1 min. A linear range from 1.46 to 36.4 mu g mL(-1) in acetate buffer solution and a detection limit of 0.11 mu g mL(-1) were achieved. In the amperometric studies, terbinafine was oxidized at +0.85 V with high throughput (225 injection h(-1)) and good linear range (10-100 mu mol L-1). It was also possible to determine the antifungal agent using simultaneous conductometric and potentiometric titrations in the presence of 5% ethanol. The electrochemical methods were applied to the quantification of TerbHCl in different tablet samples; the results were comparable with values indicated by the manufacturer and those found using titrimetry according to the Pharmacopoeia. The electrochemical methods are simple, rapid and an appropriate alternative for quantifying this drug in real samples. (C) 2012 Elsevier B.V. All rights reserved.

Assessment of Pharmaceutical Equivalence: Difference Test or Equivalence Test?

Pharmaceutical equivalence is an important step towards the confirmation of similarity and Interchangeability among pharmaceutical products, particularly regarding those that win not be tested for bioequivalence. The aim of this paper is to compare traditional difference testing to two one-side equivalence tests in the assessment of pharmaceutical equivalence, by means of equivalence studies between similar, generic and reference products of acyclovir cream, atropine sulfate injection, meropenem for injection, and metronidazole injection. All tests were performed in accordance with the Brazilian Pharmacopeia or the United States Pharmacopeia. All four possible combinations of results arise in these comparisons of difference testing and equivalence testing. Most of the former did not show significant difference, whereas the latter presented similarity. We concluded that equivalence testing is more appropriate than difference testing, what can make it a useful tool to assess pharmaceutical equivalence in products that will not be tested for bioequivalence.

Modeling the effects of pharmaceutical marketing

Successful innovation of prescription drugs requires a substantial amount of marketing support. There is, however, much concern about the effects of marketing expenditures on the demand of pharmaceutical products (Manchanda et al., Market Lett 16(3/4):293–308, 2005). For example, excessive marketing could stimulate demand for products in the absence of a fundamental need. It also has been suggested that increased marketing expenditures may reduce the price elasticity of demand and allow firms to charge higher prices (Windmeijer et al., Health Econ 15(1):5–18, 2005). In this paper, we present the outcomes of an empirical study in which we determine the effects of pharmaceutical marketing expenditures using a number of frequently used “standardized” models. We determine which models perform best in terms of predictive validity and adequate descriptions of reality. We demonstrate, among others, that the effects of promotional efforts are brand specific and that most standardized models do not provide adequate descriptions of reality. We find that marketing expenditures have no or moderate effects on demand for pharmaceutical products in The Netherlands.

A társadalmi felelősségvállalás tendenciái a gyógyszeriparban = Corporate Social Responsibility in the Pharmaceutical Industry

A gyógyszeripar egyszerre tartozik a leginkább csodált és a legtöbbet kritizált iparágak közé. Az iparág produktumai életeket menthetnek, emberek millióinak könnyítik meg az életét, és a gyógyszereknek köszönhetően számos korábbi gyilkos kór vált ismeretlenné a fejlett országokban. Mindezek mellett azonban az iparágat számos kritika is éri: túl magas árakkal dolgozik, etikátlan promóciós praktikákkal él, magára hagyja a világ szegényeit, kétes etikai hátterű klinikai kísérleteket végez, és állami intézményekkel köt háttéralkukat. A CSR koncepciójának intenzív jelenléte az iparágban többek között a fenti ellentmondásokra adott válaszként is értelmezhető (erre utalnak a későbbiekben bemutatandó kvalitatív kutatás eredményei is). Az alábbi tanulmányban arra teszek kísérletet, hogy feltárjam, a magyar gyógyszeripar szereplői hogyan látják társadalmi felelősségüket, milyen programokat valósítanak meg CSR kezdeményezéseik során. Milyen kihívások várnak a gyógyszeripari cégek vezetőire, és milyen dilemmákkal szembesülnek társadalmi felelősségvállalásuk kapcsán? Mennyiben találhatók meg a nemzetközi kutatások által feltárt nézőpontok a hazai cégek CSR interpretációiban, illetve vannak-e a magyar gyógyszeriparnak sajátosságai ebben a tekintetben? / === / The pharmaceutical industry is among the most admired and most criticized of all. The pharmaceutical products can save lives, they make the lives of millions of people lot easier, and many legendary diseases were eradicated from the world thanks to the innovations of the industry. However, the industry receives many criticisms in the same time: the big pharma is often accused of working with high prices, applying immoral marketing practices, abandoning the poor, having a no money-no cure attitude, doing ethically questionable clinical trials, etc. This contradiction can be one reason why pharmaceutical industry is among the most CSR-oriented sectors. In this paper I investigate what the CSR initiatives and activities of the pharmaceutical companies look like in Hungary. How do the managers of these firms react to the challenges of the industry? What is their perception about the contradictions described in the previous paragraph? Are there Hungarian peculiarities regarding CSR principles and actions? During research I also wanted to identify patterns of CSR activities of the Hungarian pharmaceutical firms in order to create clusters that group companies with similar characteristics.

Non-invasive, quantitative analysis of drug mixtures in containers using spatially offset Raman spectroscopy (SORS) and multivariate statistical analysis

In this paper, spatially offset Raman spectroscopy (SORS) is demonstrated for non-invasively investigating the composition of drug mixtures inside an opaque plastic container. The mixtures consisted of three components including a target drug (acetaminophen or phenylephrine hydrochloride) and two diluents (glucose and caffeine). The target drug concentrations ranged from 5% to 100%. After conducting SORS analysis to ascertain the Raman spectra of the concealed mixtures, principal component analysis (PCA) was performed on the SORS spectra to reveal trends within the data. Partial least squares (PLS) regression was used to construct models that predicted the concentration of each target drug, in the presence of the other two diluents. The PLS models were able to predict the concentration of acetaminophen in the validation samples with a root-mean-square error of prediction (RMSEP) of 3.8% and the concentration of phenylephrine hydrochloride with an RMSEP of 4.6%. This work demonstrates the potential of SORS, used in conjunction with multivariate statistical techniques, to perform non-invasive, quantitative analysis on mixtures inside opaque containers. This has applications for pharmaceutical analysis, such as monitoring the degradation of pharmaceutical products on the shelf, in forensic investigations of counterfeit drugs, and for the analysis of illicit drug mixtures which may contain multiple components.

Efficiency and productivity of Singapore’s manufacturing sector 2001-2010: An analysis using Simar and Wilson’s (2007) bootstrapped truncated approach

This paper seeks to explain the lagging productivity in Singapore’s manufacturing noted in the statements of the Economic Strategies Committee Report 2010. Two methods are employed: the Malmquist productivity to measure total factor productivity change and Simar and Wilson’s (J Econ, 136:31–64, 2007) bootstrapped truncated regression approach. In the first stage, the nonparametric data envelopment analysis is used to measure technical efficiency. To quantify the economic drivers underlying inefficiencies, the second stage employs a bootstrapped truncated regression whereby bias-corrected efficiency estimates are regressed against explanatory variables. The findings reveal that growth in total factor productivity was attributed to efficiency change with no technical progress. Most industries were technically inefficient throughout the period except for ‘Pharmaceutical Products’. Sources of efficiency were attributed to quality of worker and flexible work arrangements while incessant use of foreign workers lowered efficiency.