Abstract of the communication presented at the 3rd International Congress of CiiEM ‘Research and Innovation in Human and Health Sciences’. Campus Egas Moniz, Caparica, Portugal, June 20-22, 2018N/

Costa, Nuno F. da

Fernandes, Ana Isabel

Pinto, João F.

English

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Drug-Excipient and Drug-Drug mixtures: a pathway for the production of co-amorphous entities  Nuno F. da Costa1,2, João F. Pinto2 and Ana I. Fernandes1   1.CiiEM − Centro de Investigação Interdisciplinar Egas Moniz, Instituto Universitário Egas Moniz, Monte de Caparica, Portugal; 2 iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal.  aifernandes@egasmoniz.edu.pt  Introduction: Bioavailability is a milestone in drug development, since it reflects the amount of drug absorbed that reaches the site of action. About 70-90% of all drugs in R&D have problems regarding solubility in water, thus presenting low bioavailability (1). Consequently, high doses of drug should be present in the final dosage form to assure therapeutic effect (1), resulting in higher costs for both industry and patients. Co-amorphization is a common strategy to increase the solubility of drugs in water. The co-amorphous systems can be produced with a mixture of active pharmaceutical ingredients (APIs) or a mixture of a drug with one or more small molecular weight excipients (1,2). The purpose of this work was the production of co-amorphous entities with carbamazepine, a class II BCS drug, nearly insoluble in water (3), and the evaluation of which substances (either APIs or excipients) allowed the production of the most stable systems. Materials and Methods: Mixtures of carbamazepine with indomethacin, olanzapine, L-arginine, L-tryptophan, L-proline, citric acid, oxalic acid, tartaric acid, saccharin and caffeine were produced in a 1:1 molar ratio. The molten pairs of substances were quenched cooled with liquid nitrogen to produce the co-amorphous, which were characterized by near infrared spectroscopy (NIR, ABB TLA 20) to identify possible interactions between the compounds and differential scanning calorimetry (DSC, TA Instruments QA200) to assess the formation of amorphous or other polymorphic forms of carbamazepine.  Results: From the DSC analysis it was possible to identify that drug-drug mixtures (carbamazepine-olanzapine and carbamazepine-indomethacin) were successfully converted into co-amorphous systems. On the other hand, it was not possible to produce co-amorphous of carbamazepine with any of the excipients tested. For the carbamazepine-olanzapine and carbamazepine-indomethacin systems, the NIR spectra shows the disappearance of the peak corresponding to the CONH2 functional group of carbamazepine (5100-6800cm-1). Furthermore, for the system carbamazepine-indomethacin a decrease in the intensity of the NH and OH regions around 5000-4800cm-1, was also found.  Discussion and Conclusions: Carbamazepine was able to produce co-amorphous mixtures with either of the other drugs (olanzapine or indomethacin), while the blends comprising carbamazepine and excipients were not converted to the amorphous state. The formation of the co-amorphous system involved the formation of hydrogen bonds between the functional groups CONH2 and NH or OH, depending on which exist in the molecules. The impact of drug:drug co-amorphization on carbamazepine solubility is under evaluation.  References: 1. Rohani S., Skieneh J.M. Screening new solid forms of pharmaceuticals to enhance solubility and dissolution rate. Austin Pharmacol Pharm. 2017; 2(1):1007.  2. Dengale S.J., Grohganz H., Rades T., Löbmann K. Recent advances in co-amorphous drug formulations, Adv Drug Deliv Rev. 2016; 100:116-25.  3. Shayanfar A., Velaga S., Jouyban A., Solubility of carbamazepine, nicotinamide and carbamazepine-nicotinamide cocrystal in ethanol-water mixtures. Fluid Phase Equilibr. 2014; 363:97-105.  Acknowledgements: Fundação para a Ciência e a Tecnologia (PTDC/CTMBIO/3946/2014)  is acknowledged for funding.  

Drug-excipient and drug-drug mixtures : a pathway for the production of co-amorphous entities

Poster presented at the 3rd International Congress of CiiEM - Research and Innovation in Human and Health Sciences. Monte da Caparica, Portugal, 20-22 June 2018N/

REFERENCES 1. Rohani S., Skieneh J.M. Screening new solid forms of pharmaceuticals to enhance solubility and dissolution rate. Austin Pharmacol Pharm. 2017; 2(1):1007.  2. Dengale S.J., Grohganz H., Rades T., Löbmann K. Recent advances in co-amorphous drug formulations, Adv Drug Deliv Rev. 2016; 100:116-25.  3. Shayanfar A., Velaga S., Jouyban A., Solubility of carbamazepine, nicotinamide and carbamazepine-nicotinamide cocrystal in ethanol-water mixtures. Fluid Phase Equilibr. 2014; 363:97-105.  ACKNOWLEDGEMENT Fundação para a Ciência e a Tecnologia (PTDC/CTM-BIO/3946/2014) is acknowledged for funding. MATERIALS AND METHODS Mixtures of carbamazepine with indomethacin, olanzapine, L-arginine, L-tryptophan, L-proline, citric acid, oxalic acid, tartaric acid and saccharin were produced in a 1:1 molar ratio. The molten pairs of substances were quenched cooled with liquid nitrogen to produce the co-amorphous, which were characterized by near infrared spectroscopy (NIR, ABB TLA 2000) to identify possible interactions between the compounds and differential scanning calorimetry (DSC, TA Instruments QA200) to assess the formation of amorphous or other polymorphic forms of carbamazepine.  RESULTS AND DISCUSSION INTRODUCTION Bioavailability is a milestone in drug development, since it reflects the amount of drug absorbed that reaches the site of action. About 70-90% of all drugs in R&D have problems regarding solubility in water, thus presenting low bioavailability (1). Consequently, high doses of drug should be present in the final dosage form to assure therapeutic effect (1), resulting in higher costs for both industry and patients. Co-amorphization is a common strategy to increase the solubility of drugs in water. The co-amorphous systems can be produced with a mixture of active pharmaceutical ingredients (APIs) or a mixture of a drug with one or more small molecular weight excipients (1,2). The purpose of this work was the production of co-amorphous entities with carbamazepine, a class II BCS drug, nearly insoluble in water (3), and the evaluation of which substances (either APIs or excipients) allowed the production of the most stable systems. Nuno F. da Costa1,2,  João F. Pinto2, Ana I. Fernandes1  1CiiEM, Instituto Universitário Egas Moniz, Campus Universitário, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal,  2 iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Avenida Professor Gama Pinto 1649-003 Lisboa, Portugal  aifernandes@egasmoniz.edu.pt   DRUG-EXCIPIENT AND DRUG-DRUG MIXTURES:  a pathway for the production of co-amorphous entities From DSC analysis it was possible to identify that drug-drug mixtures (carbamazepine-olanzapine and carbamazepine-indomethacin) were successfully converted into co-amorphous systems. On the other hand, it was impossible to produce co-amorphous of carbamazepine with any of the excipients tested. For the carbamazepine-olanzapine and carbamazepine-indomethacin systems, the NIR spectra showed the disappearance of the peak corresponding to the CONH2 functional group of carbamazepine (around 5100 and 6800cm-1). Furthermore, a decrease in the intensity of the NH and OH regions around 5000-4800cm-1 was also found. -6-4-202Heat Flow (W/g)0 50 100 150 200Temperature (°C)                  Carbamazepine–––––––                  Indomethacin– – – –                  Carbamazepine_Indomethacin_(1_1)––––– ·Exo Up Universal V4.5A TA Instruments-8-6-4-202Heat Flow (W/g)0 50 100 150 200Temperature (°C)                  Carbamazepine–––––––                  Olanzapine– – – –                  Carbamazep_Olanzapine (1_1)_QC––––– ·Exo Up Universal V4.5A TA InstrumentsFig. 1. Carbamazepine molecular structure Fig. 2. DSC thermogram obtained for the system carbamazepine and olanzapine. Fig. 3. NIR spectra obtained for the system carbamazepine and olanzapine. Fig. 4. Olanzapine molecular structure. Fig. 5. DSC thermogram obtained for the system carbamazepine and indomethacin. Fig. 6. NIR spectra obtained for the system carbamazepine and indomethacin. Fig. 7. Indomethacin molecular structure. CONCLUSIONS Carbamazepine was able to produce co-amorphous mixtures with either of the other drugs (olanzapine or indomethacin), while the blends containing carbamazepine and excipients were not converted to the amorphous state. The formation of the co-amorphous system involved the formation of hydrogen bonds between the functional groups CONH2 (from carbamazepine) and NH or CO2H, depending on which exist in the molecules (olanzapine and indomethacin respectively). The impact of drug:drug co-amorphization on carbamazepine solubility is under evaluation. Heat flow (W/g) Heat flow (W/g) Absorbance Absorbance Wavenumber (1/cm) Wavenumber (1/cm) Temperatur  (ºC) Temperature (ºC) 

Drug-excipient and drug-drug mixtures: a pathway for the production of co-amorphous entities

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Drug-excipient and drug-drug mixtures : a pathway for the production of co-amorphous entities

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