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Papers by Marco Gil

L'invention concerne un procede de reduction de la taille de particules d'un principe act... more L'invention concerne un procede de reduction de la taille de particules d'un principe actif pharmaceutique (API) tout en maintenant sa forme polymorphe, le procede comprenant l'etape de traitement du principe actif pharmaceutique par cavitation a pression elevee. Le procede comprend, de preference, l'etape d'isolement du principe actif traite sous la forme de poudre, l'etape d'isolement comprenant la filtration ou le sechage par atomisation. Les particules produites par le procede de l'invention possedent typiquement une plage de valeurs inferieure a 2,5.

Molecular pharmaceutics, May 1, 2017

Our primary objective is to characterize the self-association of rafoxanide in alkaline media. Th... more Our primary objective is to characterize the self-association of rafoxanide in alkaline media. The second objective is to illustrate the feasibility of using rafoxanide micellar solution as the feed solution to prepare amorphous solid dispersion via spray drying. Rafoxanide is a poorly water-soluble drug. It is a weak acid, and its poor aqueous solubility is due to its hydrophobicity. The surface-active property of rafoxanide has not been previously reported. It was discovered that the addition of a small percentage of organic solvents is required to elevate the solubility of rafoxanide above the critical micelle concentration to allow for the formation of micelles. Our fluorescence decay study confirms the self-association of rafoxanide in a cosolvent consisting of 70%, v/v, NaOH solution and 30%, v/v, acetone. The position of each functional group in the micellar structures using the (1)H NMR technique was identified. The critical micelle concentration of rafoxanide in the cosolve...

chimica oggi/Chemistry Today, 2010

Pharmaceutical manufacturers are facing ever-growing needs of quality by design practices for the... more Pharmaceutical manufacturers are facing ever-growing needs of quality by design practices for the development of robust and predictable chemical processes. In this context, the use of modern simulation techniques has emerged as a valuable tool to cope with these demands. To illustrate the potential of this approach we will cover some of the challenges faced during process development and scale-up regarding sensitive crystallizations, gas-liquid reactions, liquid-liquid extractions and equipment design emphasizing on the mixing phenomena. The use of mixing simulation tools increases the understanding on the chemical processes during Active Pharmaceutical Ingredient (API) manufacturing. This allows chemists and process engineers to mitigate risk, achieve better performances and long lasting results. Mixing simulation tools in process development INTRODUCTION Over the past decades, pharmaceutical industries lost millions of dollars in commercial scale manufacturing due to mixing proble...

Chemical Reviews, 2015

Solubilize reagents and reactants section 3.3 a AHC means aromatic heterocycle.

Regulations, and Mitigation Gyorgy Szekely,*,† Miriam C. Amores de Sousa,‡ Marco Gil, Frederico C... more Regulations, and Mitigation Gyorgy Szekely,*,† Miriam C. Amores de Sousa,‡ Marco Gil, Frederico Castelo Ferreira,*,‡ and William Heggie* †School of Chemical Engineering & Analytical Science, The University of Manchester, The Mill, Sackville Street, Manchester M13 9PL, United Kingdom ‡Department of Bioengineering and Institute for Bioengineering and Biosciences (iBB), Instituto Superior Tećnico, Universidade de Lisboa, Avenida Rovisco Pais, 1049-001, Lisbon, Portugal Hovione FarmaCiencia SA, R&D, Sete Casas, 2674-506, Loures, Portugal

Journal of Pharmaceutical and Biomedical Analysis, 2012

The present study reports on a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method d... more The present study reports on a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method development strategy supported by design of experiments (DoE) for the trace analysis of 4dimethylaminopyridine (DMAP). The conventional approaches for development of LC-MS/MS methods are usually via trial and error, varying intentionally the experimental factors which is time consuming and interactions between experimental factors are not considered. The LC factors chosen for the DoE study include flow (F), gradient (G) and injection volume (V inj) while cone voltage (E con) and collision energy (E col) were chosen as MS parameters. All of the five factors were studied simultaneously. The method was optimized with respect to four responses: separation of peaks (Sep), peak area (A peak), length of the analysis (T) and the signal to noise ratio (S/N). A quadratic model, namely central composite face (CCF) featuring 29 runs was used instead of a less powerful linear model since the increase in the number of injections was insignificant. In order to determine the robustness of the method a new set of DoE experiments was carried out applying robustness around the optimal conditions was evaluated applying a fractional factorial of resolution III with 11 runs, wherein additional factors-such as column temperature and quadrupole resolution-were considered. The method utilizes a Phenomenex Gemini NX C-18 HPLC analytical column with electrospray ionization and a triple quadrupole mass detector in multiple reaction monitoring (MRM) mode, resulting in short analyses with a 10 min runtime. Drawbacks of derivatization, namely incomplete reaction and time consuming sample preparation, have been avoided and the change from SIM to MRM mode resulted in increased sensitivity and lower LOQ. The DoE method development strategy led to a method allowing the trace analysis of DMAP at 0.5 ng/ml absolute concentration which corresponds to a 0.1 ppm limit of quantification in 5 mg/ml mometasone furoate glucocorticoid. The obtained method was validated in a linear range of 0.1-10 ppm and presented a %RSD of 0.02% for system precision. Regarding DMAP recovery in mometasone furoate, spiked samples produced %recoveries between 83 and 113% in the range of 0.1-2 ppm.

Journal of Inorganic Biochemistry, 2009

3-Hydroxy-4-pyridinones (3,4-HP) are well known iron-chelators with applications in medicinal che... more 3-Hydroxy-4-pyridinones (3,4-HP) are well known iron-chelators with applications in medicinal chemistry, mainly associated with their high affinity towards trivalent hard metal ions (e.g. M 3+ , M = Fe, Al, Ga) and use as decorporating agents in situations of metal accumulation. The polydenticity and the extra-functionality of 3,4-HP derivatives have been explored, aimed at improving the chelating efficacy and the selectivity of the interaction with specific biological receptors. However, the ideal conjugation of both features in one molecular unity usually leads to high molecular weight compounds which can have crossing-membrane limitations. Herein, a different approach is used combining a arylpiperazine-containing bis-hydroxypyridone (H 2 L 1) with a biomimetic mono-hydroxypyridinone, ornithine-derivative (HL 2), to assess the potential coadjuvating effect that could result from the administration of both compounds for the decorporation of hard metal ions. This work reports the results of solution and in vivo studies on their chelating efficacy either as a simple binary or a ternary system (H 2 L 1 :HL 2 :M 3+), using potentiometric and spectrophotometric methods. The solution complexation studies with Fe(III) indicate that the solubility of the complexes is considerably increased in the ternary system, an important feature for the metal complex excretion, upon the metal sequestration. The results of the in vivo studies with 67 Ga-injected mice show differences on the biodistribution profiles of the radiotracer, upon the administration of each chelating agent, that are mainly ascribed to the differences of their extra-functional groups and lipo/hydrophilic character. However, administration of both chelating agents leads to a more steady metal mobilization, which may be attributed to an improved access to different cellular compartments.

Green Chem., 2013

The present paper discusses a comparative study concerning performance efficiency and sustainable... more The present paper discusses a comparative study concerning performance efficiency and sustainable impact of three purification processes for degenotoxification of Active Pharmaceutical Ingredients (APIs) post reaction streams: recrystallization, flash chromatography and organic solvent nanofiltration (OSN). Two case studies in each process were selected for evaluation of the separation technologies featuring the same model API being Mometasone furoate (Meta) glucocorticoid and two genotoxic impurities (GTIs). Methyl mesylate (MeMS) and 4-dimethylaminopyridine (DMAP) were chosen as model impurities due to their incidental appearance in glucocorticoids based on a common methanesulfonylation manufacturing step. Successful degenotoxification was achieved in all cases concerning DMAP and MeMS reaching final GTI levels below the regulatory thresholds with the exception of DMAP using recrystallization. API losses were 5% and 6.4% for OSN, 6.4% and 11.9% for flash chromatography and 14.9% and 16.4% for recrystallization during the removal of DMAP and MeMS, respectively. The API loss occurring during the purification processes has a significant impact on the outcome of cost analysis. Mass and carbon intensity values are highest for OSN and lowest for recrystallization, while flash chromatography has intermediate values. Although recrystallization is more time consuming, it should not be discarded without careful analysis since API loss often declines at larger scales and it generally gives the API in the desired crystallographic form. Solvent recycling has a significant impact on the sustainability of all the processes by the reduction of mass intensity by two orders of magnitude (from 400-1300 to 14-63 kg/ kg-API, depending on the process) and narrowing down carbon intensity to the range of 100-200 kg-CO 2 /kg-API. OSN requires the use of 7 diavolumes, therefore its high performance is achieved at the cost of high solvent usage. Hence, solvent recycling also has a higher positive environmental impact on OSN.

Drug Testing and Analysis, 2013

This paper discusses a design of experiments (DoE) assisted optimization and robustness testing o... more This paper discusses a design of experiments (DoE) assisted optimization and robustness testing of a liquid chromatographytandem mass spectrometry (LC-MS/MS) method development for the trace analysis of the potentially genotoxic 1,3diisopropylurea (IPU) impurity in mometasone furoate glucocorticosteroid. Compared to the conventional trial-and-error method development, DoE is a cost-effective and systematic approach to system optimization by which the effects of multiple parameters and parameter interactions on a given response are considered. The LC and MS factors were studied simultaneously: flow (F), gradient (G), injection volume (V inj), cone voltage (E con), and collision energy (E col). The optimization was carried out with respect to four responses: separation of peaks (Sep), peak area (A p), length of the analysis (T), and the signal-to-noise ratio (S/N). An optimization central composite face (CCF) DoE was conducted leading to the early discovery of carry-over effect which was further investigated in order to establish the maximum injectable sample load. A second DoE was conducted in order to obtain the optimal LC-MS/MS method. As part of the validation of the obtained method, its robustness was determined by conducting a fractional factorial of resolution III DoE, wherein column temperature and quadrupole resolution were considered as additional factors. The method utilizes a common Phenomenex Gemini NX C-18 HPLC analytical column with electrospray ionization and a triple quadrupole mass detector in multiple reaction monitoring (MRM) mode, resulting in short analyses with a 10-min runtime. The high sensitivity and low limit of quantification (LOQ) was achieved by (1) MRM mode (instead of single ion monitoring) and (2) avoiding the drawbacks of derivatization (incomplete reaction and time-consuming sample preparation). Quantitatively, the DoE method development strategy resulted in the robust trace analysis of IPU at 1.25 ng/mL absolute concentration corresponding to 0.25 ppm LOQ in 5 g/l mometasone furoate glucocorticosteroid. Validation was carried out in a linear range of 0.25-10 ppm and presented a relative standard deviation (RSD) of 1.08% for system precision. Regarding IPU recovery in mometasone furoate, spiked samples produced recoveries between 96 and 109 % in the range of 0.25 to 2 ppm.

AAPS Advances in the Pharmaceutical Sciences Series, 2016

A set of three N-carboxyalkyl 3-hydroxy-4-pyridinones has been studied as bidentate M(III) chelat... more A set of three N-carboxyalkyl 3-hydroxy-4-pyridinones has been studied as bidentate M(III) chelators (M5Fe, Al, Ga), with potential for oral administration. After preparation of the ligands, their protonation constants (log K ) and the stability constants of their metal i complexes have been determined. The distribution coefficients of these compounds, between 1-octanol and Tris buffer pH 7.4, were 67 measured. The effect of these compounds on the biodistribution of Ga-citrate loaded rats was investigated and compared with that of the 67 administered Ga-complexes. Results indicated that, among these chelating agents, the N-carboxyethyl derivative has the highest affinity towards this set of metal ions, irrespective of the metal, and that it could even compete with transferrin, the main Fe-plasma protein. The binding affinity and the hydrophilic character decrease with the increase in the size of the alkylic chain. The biological assays indicate that the complex formation in vivo is ...

AAPS Advances in the Pharmaceutical Sciences Series, 2011

Journal of Inorganic Biochemistry, 2002