Bernard Do

Benzocaine polymorphism: Pressure-temperature phase diagram involving forms II and III

Understanding the phase behavior of an active pharmaceutical ingredient in a drug formulation is required to avoid the occurrence of sudden phase changes resulting in decrease of bioavailability in a marketed product. Benzocaine is known to possess three crystalline polymorphs, but their stability hierarchy has so far not been determined. A topological method and direct calorimetric measurements under pressure have been used to construct the topological pressure-temperature diagram of the phase relationships between the solid phases II and III, the liquid, and the vapor phase. In the process, the transition temperature between solid phases III and II and its enthalpy change have been determined. Solid phase II, which has the highest melting point, is the more stable phase under ambient conditions in this phase diagram. Surprisingly, solid phase I has not been observed during the study, even though the scarce literature data on its thermal behavior appear to indicate that it might be the most stable one of the three solid phases.

Enantiomer resolution by pressure increase: inferences from experimental and topological results for the binary enantiomer system (R)- and (S)-mandelic acid.

In pharmacy, racemic compounds are often problematic, because generally only one of the enantiomers possesses therapeutic activity and it is often difficult to separate them. Even though this problem is likely as old as the pharmaceutical industry, one thermodynamically obvious way of separating racemic crystals has never been studied experimentally, which is by using pressure. Data have been obtained on the equilibria of the (R)- and (S)-mandelic acid system as a function of pressure and temperature. With the use of thermodynamic arguments including the Clapeyron, Schröder, and Prigogine-Defay equations, it has been demonstrated that the conglomerate (crystals of separated enantiomers) becomes more stable than the racemic compound at approximately 0.64 GPa and 460 K. Even though this pressure is still higher than at the bottom of the Mariana Trench, there are no technical obstacles to produce such conditions, making pressure a viable option for separating enantiomers.

Dimorphism of the prodrug l‐tyrosine ethyl ester: Pressure–temperature state diagram and crystal structure of phase II

Polymorphism is important in the field of solid-state behavior of drug molecules because of the continuous drive for complete control over drug properties. By comparing different structures of a series of L-tyrosine alkyl esters, it became apparent that the ethyl ester possesses dimorphism. Its structure was determined by powder diffraction and verified by density functional theory calculations; it is orthorhombic, P2(1) 2(1) 2(1) with a = 12.8679(8) Å, b = 14.7345(7) Å, c = 5.8333 (4) Å, V = 1106.01(11) Å, and Z = 4. The density of phase II is in line with other tyrosine alkyl esters and its conformation is similar to that of l-tyrosine methyl ester. The hydrogen bonds exhibit similar geometries for phase I and phase II, but the H-bonds in phase I are stronger. The solid II-solid I transition temperature is heating-rate dependent; it levels off at heating rates below 0.5 K min(-1), leading to a transition temperature of 306 ± 4 K. Application of the Clapeyron equation in combination with calorimetric and X-ray data has led to a topological diagram providing the relative stabilities of the two solid phases as a function of pressure and temperature; phase II is stable under ambient conditions.

Overall stability for the ibuprofen racemate: experimental and topological results leading to the pressure-temperature phase relationships between its racemate and conglomerate.

Enantiomer resolution is much sought after for pharmaceutical applications, because many optically active drug molecules have only one pharmaceutically active enantiomer. Although it is always possible to force separation, it will come at a cost. The present method, based on thermodynamics, provides a relatively easy approach to investigate whether separation can be thermodynamically spontaneous. A topological phase diagram of the binary enantiomer system at 0.5 mol-fraction is constructed as a function of temperature and pressure after analysis of pressure and heat related quantities. It is demonstrated that for ibuprofen, an optically active analgesic, the racemate is the only stable solid form; the phase relationship between the racemate and the conglomerate is analogous to dimorphism with overall monotropy in pure chemical compounds.

Liquid chromatography with tandem mass spectrometry for the simultaneous identification and quantification of cardiovascular drugs applied to the detection of substandard and falsified drugs

The counterfeiting of pharmaceuticals has been detected since about 1990 and has alarmingly continued to pick up steam. We have been recently involved in an evaluation program of some of the most commonly prescribed cardiovascular drugs in Africa, for analysing an important number of tablets or capsules obtained from different places in seven African countries. A reversed-phase high-performance liquid chromatography with tandem mass spectrometry method was developed and validated to simultaneously control the identity and the quantity of acenocoumarol, amlodipine, atenolol, captopril, furosemide, hydrochlorothiazide and simvastatin in tablets. Their separation was performed on a Kinetex® C(18) (100 mm × 2.1 mm inside diameter, 2.6 μm) column using a gradient elution of 20 mM ammonium formate buffer and acetonitrile (90:10 10:90 v/v) at a flow rate of 0.5 mL/min. The analytes were detected using electrospray ionisation tandem mass spectrometry in both positive and negative modes with multiple reaction monitoring. Tandem mass spectrometry fragmentation patterns of captopril, furosemide and acenocoumarol, up to now not detailed in the literature, were also studied to assist in the selection of the most relevant transitions towards the objectives. The developed method was validated as per International Conference on Harmonisation guidelines with respect to specificity, linearity, trueness, precision, limits of detection and quantification. It has been successfully applied to the control of oral forms of seven cardiovascular drugs collected in African countries.

Identification of the major degradation pathways of ticagrelor

Ticagrelor is a direct-acting and reversible P2Y12-adenosine diphosphate (ADP) receptor blocker used as antiplatelet drug. Forced degradation under various stress conditions was carried out. The degradation products have been detected and identified by high-pressure liquid chromatography multistage mass spectrometry (LC-MS(n)) along with high-resolution mass spectrometry. C18 XTerra MS column combined with a linear gradient mobile phase composed of a mixture of 10 mM acetate ammonium/acetonitrile was shown suitable for drug and impurity determinations and validated as a stability indicating method. Structural elucidation of the degradation products relied on MS(n) studies and accurate mass measurements giving access to elemental compositions. Up to nine degradation products resulting from oxidation/auto-oxidation, S-dealkylation and N-dealkylation have been identified, covering a range of possible degradation pathways for derivatives with such functional groups. Kinetics was also studied in order to assess the molecules shelf-life and to identify the most important degradation factors.

An Integrated View of the Influence of Temperature, Pressure, and Humidity on the Stability of Trimorphic Cysteamine Hydrochloride

Understanding the phase behavior of pharmaceuticals is important for dosage form development and regulatory requirements, in particular after the incident with ritonavir. In the present paper, a comprehensive study of the solid-state phase behavior of cysteamine hydrochloride used in the treatment of nephropathic cystinosis and recently granted orphan designation by the European Commission is presented employing (high-pressure) calorimetry, water vapor sorption, and X-ray diffraction as a function of temperature. A new crystal form (I2/a, form III) has been discovered, and its structure has been solved by X-ray powder diffraction, while two other crystalline forms are already known. The relative thermodynamic stabilities of the commercial form I and of the newly discovered form III have been established; they possess an overall enantiotropic phase relationship, with form I stable at room temperature and form III stable above 37 °C. Its melting temperature was found at 67.3 ± 0.5 °C. Cysteamine hydrochloride is hygroscopic and immediately forms a concentrated saturated solution in water with a surprisingly high concentration of 47.5 mol % above a relative humidity of 35%. No hydrate has been observed. A temperature-composition phase diagram is presented that has been obtained with the unary pressure-temperature phase diagram, measurements, and calculations. For development, form I would be the best form to use in any solid dosage form, which should be thoroughly protected against humidity.

Quality Assessment of 7 Cardiovascular Drugs in 10 Sub-Saharan Countries: The SEVEN Study

Quality Assessment of 7 Cardiovascular Drugs in 10 Sub-Saharan Countries: The SEVEN Study Substandard and falsified medicines pose a serious threat to patient safety and public health.1 Studies on the quality of drugs have focused mainly on antimicrobial agents, such as antiretroviral therapy (for human immunodeficiency virus) and antimalarial medications.2 Although cardiovascular disease kills millions of Africans,3 to our knowledge, little published research has explored the quality of essential cardiovascular disease medicines to date. We therefore performed a quality assessment of 7 commonly used cardiac drugs (ie, an anticoagulant drug, a statin, and 5 antihypertensive drugs) in 10 countries of sub-Saharan Africa.

Identification of dabigatran etexilate major degradation pathways by liquid chromatography coupled to multi stage high-resolution mass spectrometry

Dabigatran etexilate (DABET) is an oral direct thrombin inhibitor that has been approved for the prevention of blood clot formation. As the active pharmaceutical ingredient (API) may undergo degradation, leading to drug activity loss or to the occurrence of adverse effects associated with degradation products, thorough knowledge of the APIs stability profile is required. Since very few studies have been reported on the drug stability profile, a study related to DABETs behaviour under stress conditions was carried out in order to identify its major degradation pathways. DABET was subjected to hydrolytic (acidic and alkaline), oxidative, photolytic and thermal stress, as per ICH-specified conditions. Up to ten degradation products along with dabigatran, the active metabolite of DABET, were formed and detected by reverse phase liquid chromatography in gradient mode (LC) coupled to UV and mass spectrometry (UV-MS). Structures were determined by elemental composition determination and study of the fragmentation patterns, using high-resolution mass spectrometry in multistage mode (HR-MSn). Under hydrolytic stress conditions, O-dealkylation may occur and formation of benzimidic acid derivatives was also observed. DABET was shown to be much less susceptible to photolysis and oxidative stress, even if N-dealkylation was highlighted. In view of the structures identified, various degradation pathways of DABET have been proposed.

Phototransformation patterns of the antiplatelet drug tirofiban in aqueous solution, relevant to drug delivery and storage

Tirofiban is a synthetic, nonpeptidic fibrinogen receptor antagonist used as an antiplatelet drug for intravenous delivery. As the active pharmaceutical ingredient may undergo light exposure during manufacturing, storage and/or delivery, there is a need to acquire an extensive knowledge of its major photochemical-degradation pathways. Thus, photochemical-degradation of tirofiban under simulated light irradiation in aqueous solution and in the absence of photosensitizers or photocatalysts, has been investigated in terms of mechanisms. The structural characterization of the photochemical products was carried out with using performance liquid chromatography-multistage high-resolution mass spectrometry along with on-line hydrogen/deuterium exchange. The identification of the twelve detected photochemical products suggested that the photo-transformation of tirofiban occurred via multiple reaction pathways, initiated either by electron or hydrogen atom transfer. These included the photo-oxidation of the piperidine moiety without impacting the secondary amine, the hydroxylation of the methylene group activated by the aromatic ring, the oxidation of the alkyl-sulfonamide group and also the decarboxylative oxidation of the molecule. Hydroxylated compounds, geminal and vicinal-diol compounds, were highlighted suggesting that most of the photoproducts are more hydrophilic than the drug. Understanding the main photo-degradation routes is a good basis to work out efficient measures so as to mitigate or avoid tirofiban instability.