approach for discriminating activepharmaceuticalingredient origins: example of simvastatin RESUME
Le contrôle qualité des matières premières entrant dans la fabrication des produits finis pharmaceutiques est considéré comme primordial par l’industrie pharmaceutique et les agences de régulation. Ainsi, une méthode analytique permettant de déterminer l’origine des principes actifs dans les matières premières et produits finis est présentée dans ce document. Cette méthode, combinant analyse multivariée et profils d’impuretés obtenus par chromatographie liquide haute performance couplée à la spectrométrie de masse en tandem par analyseur hybride quadripôle – temps de vol (LC-MS/MS QTOF), a été mise en œuvre sur 49 échantillons de matières premières et produits finis contenant la substance active hypolipidémiante simvastatin. L’extrême sensibilité de la technique LC-MS/MS QTOF a permis l’identification de 4 nouvelles substances apparentées non répertoriées dans la monographie correspondante. L’analyse en composantes principales, basée sur un modèle à 6 variables et 28 observations, exprimait 92,2% de la variance, après trois composantes, et affichait un coefficient de prédiction de 60%. Les résultats obtenus ont permis de discriminer sans ambiguïté entre 11 fournisseurs distincts, confirmant la capacité de la méthode combinant chimiométrie et profils d’impuretés LC-MS/MS QTOF à distinguer entre différentes origines de principe actif.
2 Université de Toulouse, École des Mines d’Albi, CNRS, Centre RAPSODEE, F-81013 Albi, France
The plasticising effect of supercritical CO 2 during the solvent-free melt extrusion of the cationic copolymer
Eudragit E and the heat-sensitive and slowly dissolving activepharmaceuticalingredient, spironolactone was shown to reasonably improve the purity of the prepared solid dispersions by enabling production at lower temperature ranges. By increasing the mass flow of the melt, further enhancement was achieved in purity, but the shorter residence time counteracted the amorphisation (i.e. molecular dispersion) of crystalline drug particles, according to data acquired by confocal Raman mapping. At the same time, supercritical CO 2 aided
RESULTS AND DISCUSSION
Comparison of the melt and supercritical CO2‐aided extrusion techniques
To improve the dissolution rate of CAR by forming solid dispersion or solution of the drug in the E100 matrix, both melt extrusion and scCO2 ‐aided melt extrusion processes were performed (Table 1). The viscosity of the material in the barrel was correlated with the torque. Without the injection of scCO2, the maximum applicable rotation speed was 5 rpm. In contrast, while injecting scCO2, the torque signiﬁcantly decreased, and the rotation speed could be increased stepwise up to 10 rpm. The torque at 10 rpm was lower than the value corresponding to 5 rpm without scCO2 (Fig. 4). This is demonstrated by experi- ments 2 and 5 at 5% of CAR and 6 and 9 at 20% of CAR. A gain in the maximal throughput, from 5.5 to 11 g/min (cf. Table 1), was also observed as well as a shortened residence time. These effects are consistent with a lower viscosity, which can be attributed to the plasticization effect of carbon dioxide. The application of scCO2 in the ﬁeld of pharmaceutical extrusion has two noteworthy advantages as for the CAR stability point of
2 Bio-Pharmaceutical and Toxicological Analysis Research Team, Laboratory of
Pharmacology and Toxicology, Faculty of Medicine and Pharmacy, University Mohammed V, Rabat, Morocco
Handheld Raman spectroscopy is actually booming. Recent devices aim at addressing the usual Raman spectroscopy issues: fluorescence with shifted‐excitation Raman difference spectroscopy (SERDS), poor sensitivity with surface enhanced Raman scattering (SERS) and only surface information with spatially offset Raman spectroscopy (SORS). While qualitative performances of handheld devices are generally well established, the quantitative analysis of pharmaceutical samples remain challenging.
Determination of Eflucimibe solubilisation ki- netics
The Eflucimibe solubilisation kinetics were de- termined with samples corresponding to 50 mg of Eflucimibe. These samples were added to 100 ml of the solubilisation medium corresponding to an aque- ous solution containing 5 % (w/V) of sodium lauryl sulfate. The samples were continously stirred while remaining in a water bath at 310 K (normalized tem- perature for pharmaceutical test). At various time in- tervals, samples were withdrawn and filtered through 0.45μm membrane. The amount of Eflucimibe dis- solved was determined by HPLC using UV detection at 220 nm. Acetonitrile and purified water at 82 : 18 V/V was run at 1ml.min -1 flow rate through a reverse
The parties do not appear to have raised the argument that the ICA’s decision is arguably at odds with the compe- tition law regime governing the licensing of intellectual property rights in that it raises doubts about the ability of pharmaceutical companies to license out their rights for specific fields of use. In this case, Roche’s subsidiary, Gen- entech developed Avastin and Lucentis. Roche decided to license Lucentis out to Novartis for the treatment of eye disease and to commercialise Avastin itself for the treat- ment of cancer. Under the Technology Transfer Guidelines, the restriction on the sale of Lucentis and Avastin outside of their intended therapeutic areas could have been achieved by placing field-of-use restrictions in the licence agreement. 40 Indeed, field-of-use restrictions are pro-com- petitive to the extent that they encourage the dissemination of technology by allowing a licensor to use its technology for one use and to license it out for another.
Perhaps the most troubling aspect of the monitoring report is that the categories used to classify settlements in terms of the degree of competition law risk attached to them provide little useful information and arguably have a chilling effect on settlements that could be pro- competitive to the extent that they would allow early generic entry. These categories had their origin in the Commission’s Report on the Pharmaceutical Sector Inquiry, which is somewhat ironic given that, in this Report, the Commission explicitly disavowed reaching any conclusions concerning the application of competi- tion law in the pharmaceutical sector. 21 Settlements fall- ing in Category A and Category B.I are considered to be generally unproblematic, which is not surprising as Category A settlements are those that allow immediate market entry by the generic, and those in Category B.I are those where there is no value transfer from the ori- ginator, i.e. where the generic agrees to enter after patent expiry. It is questionable whether settlements in these categories are settlements at all in the sense that the one side or the other has capitulated entirely.
Fourth, the panel of journals that we choose was not proved to be representative of pharmaceutical international journals; we selected journals on a practical considerations basis (availability in our University library). Even, some issues of Am J Health-System Pharm were not included because they vanished from the library before being examined.
A potential bias is the lack or the low number of pharmaceutical colleges in universities of some countries (i.e.: Belgium, Luxemburg, Russia ), which could draw pharmacists researchers to work in medical or scientific universities. This could impeach such people to be …
The comparison of experimental and calculated values for crystal size distribution revealed that neither a plug flow model nor an axial dispersion model could describe accurately the continuous crystallization process, as both models yielded a crystal size distribution narrower than the experimental data. A growth rate dispersion model showed a reasonable agreement to describe the size spreading of the crystal size distribution. Collision of crystals with each other and with mixing elements inside the crystallizer may be the source of random fluctuation of the growth rate in the non-conventional plug flow crystallizer with static mixers. The adequate combination of experimental data and a mathematical model help to analyze and understand the combined effect of crystal growth and nucleation in the continuous crystallizer. These results have an important relevance for the pharmaceutical industry, as there is an increased interest in development of continuous crystallization processes.
(QC) remain mandatory, the improvements provided by QbD should lead to the production of less “bad products” since the mechanisms leading to this quality are known.
In the pharmaceutical industry, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), that regroups experts from the pharmaceutical field and regulatory authorities from Europe, Japan and United States, has clearly understood the gains of such ap- proaches when applied to pharmaceutical processes, in which analytical methods are obviously involved. The ICH releases regulatory documents that are adopted by countries as laws or guidelines. The work of ICH is classified in four topics: the quality (Q), the safety (S), the efficiency (E), and some multidisciplinary (M) topics. In the present work, the focus is put on the first topic, the quality, with the objective to facilitate the analytical method development in a QbD environment. It will be shown how the ICH requirements can be applied for several applications involving analytical methods.
A pharmaceutical company is facing instability in the planning process. Using analysis of real data, Root Cause Analysis, and interviews in the field, the thesis aims to investigate the main causes that are leading to this situation and propose solutions for improvements that could help the company to achieve appropriate stability levels.
Figure 10. Overview of the pharmaceutical applications of molecular tweezers, clefts and clips.
4.3. What are the Next Steps for Pharmaceutical Development of Molecular Tweezers?
The past years have focused the efforts on optimizing the structure, to gain in selectivity and affinity for their biological targets. Such feature is definitely an asset for drug development, since it ensures a good efficiency and would limit the off-target or side effects. It has to be noted that the synthesis of such structures is already a challenge in itself because the 3-D structure is so precise that it might not suffer a variation of one or few atoms. The next challenges would concern their successful translation in vivo. While Klarner’s molecular tweezer CLR01 proved to be potent in the treatment of various amyloidogenic diseases and showed to be safe in animals , many synthetic receptors active in living cells failed to achieve the same efficacy in vivo . Indeed, the ability of the drug to reach their target in vivo rely on their biopharmaceutical properties, also called drug-like properties. Determined early in the drug development process, such properties help the selection of promising drug candidates, which would display favorable absorption properties, as well as distribution, metabolism and excretion, among others. Few studies have focused on these parameters, except for CLR01, which describes its pharmacokinetics and brain toxicity profile . Noteworthy, the temperature might also be a critical parameter, since the in vitro binding studies are usually carried out at room temperature and might not represent what is occurring in living animals.
The Court also afﬁrmed that the ICA was correct in examining Aspen’s pricing negotiations with the Italian Medicines Agency (AIFA) as part of its determination of abuse of dominance. The ICA had concluded that Aspen had used an aggressive negotiating strategy, leveraging its market position, to force AFIA to accept its excessive prices. Aspen had ﬁrst demanded that the cancer drugs be reclassiﬁed as non-reimbursable. When this approach failed, it threatened to withdraw the products from the market unless the prices were substantially increased. The Court clariﬁed that, while Aspen did not violate the regulatory rules themselves, Aspen ’s interactions with AIFA consisted of a ‘con- scious use of the negotiating tool’ to abuse its domin- ant position. Speciﬁcally, Aspen’s negotiating strategy was ‘expressive of the ultimate aim of taking advantage of its market power … to impose unfair prices’. Pharmaceutical companies will therefore need to take into account the possible competition law risk in deter- mining how aggressive a stance to take in pricing negotiations.
Multi-armed Bandit for Active Learning. To our knowledge there has been only two papers bridging the world of active learning and MAB.  adapted the EXP4 algorithm which is a MAB algorithm with expert advice, where the different active learning algorithms are the various experts and the different points in the pool are the arms of the MAB. An each iteration, every expert provides a sampling distribution on the pool. EXP4 maintains an estimation of the error rate for each expert, and uses exponential weight to select the optimal sampling distribution on the pool. Authors in  propose an adaptation of UCB called LCB algorithm, the authors suggested minimizing an unbiased estimator of risk of h, and a sampling distribution that was in proportion to the entropy of the prediction on the pool. The authors consider the arms of the bandit as the different hypothesis, and querying a data point, as the process of improving their estimation of the risk of the different hypothesis.