@conference{
author = "Pešić, Nikola and Dapčević, Aleksandra and Ivković, Branka and Barudžija, Tanja and Krkobabić, Mirjana and Ibrić, Svetlana and Medarević, Đorđe",
year = "2021",
abstract = "INTRODUCTION
The development of formulations with amorphous form of drug is one of the most commonly used approaches for improving solubility and bioavailability of poorly soluble drugs. Solid dispersions with different hydrophilic polymers have been widely investigated during the last decades as an approach for development of stable formulations with amorphous drug. However, high weight percentage of polymer is usually required to ensure molecular mixing with drug and stability against drug recrystallization, making difficult formulation of final dosage form [1]. In the last years, formulations of co-amorphous systems, where amorphous drug is stabilized with low molecular weight components (drug or excipient) have been successfully used for improving solubility and bioavailability of poorly soluble drugs, with overcoming limitations of solid dispersions [2]. This study investigated effect of three amino acids (AAs) on amorphization of carvedilol (CRV) by dry milling process, with the overall aim to improve CRV dissolution.
EXPERIMENTAL METHODS
Materials
CRV (Hemofarm a.d., Serbia) was used as a model poorly soluble drug. L-tryptophan (TRY, Carl Roth, Germany), L-phenylalanine (PHE, Carl Roth, Germany) and L-lysine (LYS, Acros Organics, Belgium) were used as AAs.
Samples preparation and physicochemical characterization
Mixture of CRV and each of AAs in CRV:AAs molar ratios 1:0.5, 1:1 and 1:2 were placed in 125 ml stainless steel milling jar and subject to milling in high-energy planetary ball mill (PM 100, Retch, Germany) during 4 h, with 30 min break after 2 h. Milling was performed using 10 milling balls of 10 mm diameter with rotation speed of mill of 400 rpm.
Changes of CRV and AAs physical state due to milling were assessed by Powder X-ray Diffraction (PXRD, Philips PW1050, The Netherlands) and Differential Scanning Calorimetry (DSC, DSC 1, Mettler Toledo, Germany). In vitro dissolution testing was performed under non-sink conditions using rotating paddle apparatus (Erweka DT70, Erweka, Germany). Samples containing 100 mg of CRV were tested in 250 ml of phosphate buffer (pH=6.8) during
8 h, with paddle rotation speed of 50 rpm. Concentration of dissolved CRV was determined by HPLC (Dionex Ultimate 3000, Thermo scientific, USA). Area under dissolution curve (AUC) was calculated for each formulation and compared with AUC of CRV dissolution profile.
RESULTS AND DISCUSSION
Presence of diffraction peaks at 6.0, 15.0, 17.65, 18.55 and 24.5° 2θ and sharp melting endotherm at 116.6 °C confirmed that raw CRV was present in crystalline polymorph form II [3]. Significant reduction in crystallinity was observed for all samples prepared with TRY and PHE, while there were no peaks of CRV and AA on the PXRD pattern of CRV:TRY 1:2 sample. This was confirmed by the DSC analysis, where melting peaks of CRV and AAs were present on the thermograms of all samples except CRV:TRY 1:2 sample. This sample showed only exotherm at 102 °C due to recrystallization of TRY, followed by its melting at 266 °C, confirming CRV amorphization induced by milling. High crystallinity on PXRD patterns of all samples milled with LYS, together with the presence of melting peaks of both CRV and AA on the DSC thermograms, showed that LYS was the least suitable AA for amorphization of CRV. Despite that TRY and PHE induced partial or complete amorphization of CRV, these AAs were less efficient in improving dissolution of CRV compared to LYS. The highest supersaturation of CRV was achieved from CRV:LYS 1:1 sample with almost 3 times higher AUC compared to pure CRV. It is evident that maximum CRV concentration from this sample was reached in the first 90 min and is maintained during the entire test. Although similar CRV concentration was achieved after 60 min for CRV:LYS 1:2 sample, it is evident that CRV concentration started to decrease after this time point.
CONCLUSION
Complete amorphization was achieved by milling of only CRV:TRY 1:2 mixture, while significant decrease in crystallinity was observed for other samples milled with TRY and PHE. Although milling of CRV with LYS resulted in samples with the highest crystallinity, samples prepared with this AA in 1:1 and 1:2 molar ratios were the most efficient in providing CRV supersaturation. CRV:LYS 1:1 molar ratio can be considered as optimal, as achieved supersaturation was maintained during 8 h.",
publisher = "International Association for Pharmaceutical Technology, Mainz, Germany",
journal = "12th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, 11-14 May 2021, Vienna, Austria, Virtual meeting",
title = "Evaluation of potential of amino acids for amorphization and dissolution improvement of carvedilol",
pages = "1-2",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5327"
}
