Microenvironmental pH-modified solid dispersions for improving dissolution rate of valsartan
Abstract
INTRODUCTION
Formulation of solid dispersions (SDs) with water soluble polymers is one of the most efficient approaches for improving the dissolution rate of poorly soluble drugs. However, this formulation approach might not always be effective in improving the dissolution rate of drugs, especially those with pH-dependent solubility (1). The addition of alkalizers or acidifiers can solve this problem by changing pH in the near vicinity of drug particle surface, (microenvironmental pH) to the range where drug easily dissolves (2). This study evaluated the potential of several alkalizers for improving the dissolution rate of weakly acidic drug valsartan (VAL) from SDs prepared with hydrophilic polymers.
EXPERIMENTAL METHODS
Materials
VAL (Hemofarm a.d., Serbia) was used as a model poorly soluble drug. Hypromellose (HPMC E5, MethocelTM E5 LV premium, Dow Chemicals, USA) and polyvinylpyrrolidone (PVPK25, Kollidon® 25, BASF, Germany) were used as hydrophilic polymers for SDs preparation.... Calcium oxide (CaO), magnesium oxide (MgO), sodium carbonate (Na2CO3) and meglumine (MEG) were used as alkalizers in solid dispersions.
SDs preparation
SDs were prepared in VAL:polymer:alkalizer (V:P:A) weight ratios 1:2:0.5, 1:2:1 and 1:2:2 (Table 1.). Additionally, binary SDs were prepared with VAL and polymer, but without alkalizer. VAL and polymer were dissolved in absolute ethanol on a magnetic stirred followed by dispersion of alkalizer. Ethanol was evaporated from dispersion using rotary evaporator (Büchi Rotavapor®, Büchi Labortechnik AG, Switzerland) at 50 °C. After further vacuum drying, mass was pulverized and sieved through sieve 355 μm.
SDs characterization
FT-IR spectroscopy (Nicolet iS10, Thermo Scientific, USA) was used to detect the presence of intermolecular interactions between drug, polymer and alkalizer. In vitro drug dissolution testing was performed using a rotating paddle apparatus in 900 ml of 0.1 M HCl as a dissolution medium, due to poor solubility of VAL in this medium. Microenvironmental pH (pHM) was estimated by measuring of pH of concentrated suspension of SD as an indicator of pH near the surface of drug particles.
RESULTS AND DISCUSSION
Slow and incomplete dissolution of VAL was observed from binary SDs with either PVP or HPMC. The addition of alkalizer resulted in a significantly improved VAL dissolution rate from SDs with both polymers, with faster VAL release from SDs with PVP. Na2CO3 showed the best performance in improving VAL dissolution rate amongst all tested alkalizers. Desired immediate release of VAL (>80% of VAL dissolved after 30 min) was achieved only from formulations SD8 and SD12 prepared with Na2CO3 in 1:2:1 and 1:2:2 V:P:A ratios, and also from formulation SD6 prepared with CaO in 1:2:1 V:P:A ratio). The addition of all alkalizers resulted in higher pHM (Table 1), independently of polymer used, but with considerable differences amongst tested alkalizers. The highest efficiency of Na2CO3 in improving VAL dissolution rate was not correlated with measured pHM, as higher pHM was measured for samples with CaO and MgO. However, the lowest pHM measured for samples with MEG was in accordance with the lowest capacity of this alkalizer to improve VAL dissolution rate. Due to the fastest VAL release achieved, SDs with PVP K25 and CaO or Na2CO3 were further characterized by FT-IR spectroscopy to detect the presence of intermolecular interactions in comparison with binary VAL:PVP SD (SDP) and corresponding physical mixtures (PMs). Shifting and decrease in intensity of VAL absorption band at 1729 cm-1 (carboxyl C=O stretching) and disappearance of peak at 1599 cm-1 (amide C=O stretching) was observed on the spectra of binary VAL:PVP SD compared to PM of equivalent composition, indicating that both C=O groups of VAL can be involved in intermolecular interaction with PVP. The same region of FT-IR spectra was changed in the case of SDs with alkalizer, where peak at 1729 cm-1 disappeared, while peak at 1599 cm-1 was reduced in intensity. Therefore, the same kind of interactions was observed for both binary and ternary SDs, which cannot explain observed faster VAL dissolution rate from ternary SDs with alkalizer.
CONCLUSION
The addition of alkalizer resulted in significantly improved VAL dissolution rate from SDs prepared with HPMC and PVP, wherein Na2CO3 showed the best performance amongst all tested alkalizers. Since slightly higher pHM was achieved with CaO and MgO, higher efficiency of Na2CO3 can be ascribed to its higher solubility which enables generation of pores in SDs, while release of carbon dioxide facilitates dispersion of particles in the dissolution medium and reduces their tendency towards aggregation.
Source:
12th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, 11-14 May 2021, Vienna, Austria, Virtual meeting, 2021, 1-2Publisher:
- International Association for Pharmaceutical Technology, Mainz, Germany
Funding / projects:
- Advanced technologies for controlled release from solid drug delivery systems (RS-MESTD-Technological Development (TD or TR)-34007)
Note:
- 12th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, Virtual meeting, Live event from 11 - 14 May 2021, Vienna, Austria
Collections
Institution/Community
PharmacyTY - CONF AU - Medarević, Đorđe AU - Dobričić, Vladimir AU - Krkobabić, Mirjana AU - Pešić, Nikola AU - Ibrić, Svetlana PY - 2021 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5326 AB - INTRODUCTION Formulation of solid dispersions (SDs) with water soluble polymers is one of the most efficient approaches for improving the dissolution rate of poorly soluble drugs. However, this formulation approach might not always be effective in improving the dissolution rate of drugs, especially those with pH-dependent solubility (1). The addition of alkalizers or acidifiers can solve this problem by changing pH in the near vicinity of drug particle surface, (microenvironmental pH) to the range where drug easily dissolves (2). This study evaluated the potential of several alkalizers for improving the dissolution rate of weakly acidic drug valsartan (VAL) from SDs prepared with hydrophilic polymers. EXPERIMENTAL METHODS Materials VAL (Hemofarm a.d., Serbia) was used as a model poorly soluble drug. Hypromellose (HPMC E5, MethocelTM E5 LV premium, Dow Chemicals, USA) and polyvinylpyrrolidone (PVPK25, Kollidon® 25, BASF, Germany) were used as hydrophilic polymers for SDs preparation. Calcium oxide (CaO), magnesium oxide (MgO), sodium carbonate (Na2CO3) and meglumine (MEG) were used as alkalizers in solid dispersions. SDs preparation SDs were prepared in VAL:polymer:alkalizer (V:P:A) weight ratios 1:2:0.5, 1:2:1 and 1:2:2 (Table 1.). Additionally, binary SDs were prepared with VAL and polymer, but without alkalizer. VAL and polymer were dissolved in absolute ethanol on a magnetic stirred followed by dispersion of alkalizer. Ethanol was evaporated from dispersion using rotary evaporator (Büchi Rotavapor®, Büchi Labortechnik AG, Switzerland) at 50 °C. After further vacuum drying, mass was pulverized and sieved through sieve 355 μm. SDs characterization FT-IR spectroscopy (Nicolet iS10, Thermo Scientific, USA) was used to detect the presence of intermolecular interactions between drug, polymer and alkalizer. In vitro drug dissolution testing was performed using a rotating paddle apparatus in 900 ml of 0.1 M HCl as a dissolution medium, due to poor solubility of VAL in this medium. Microenvironmental pH (pHM) was estimated by measuring of pH of concentrated suspension of SD as an indicator of pH near the surface of drug particles. RESULTS AND DISCUSSION Slow and incomplete dissolution of VAL was observed from binary SDs with either PVP or HPMC. The addition of alkalizer resulted in a significantly improved VAL dissolution rate from SDs with both polymers, with faster VAL release from SDs with PVP. Na2CO3 showed the best performance in improving VAL dissolution rate amongst all tested alkalizers. Desired immediate release of VAL (>80% of VAL dissolved after 30 min) was achieved only from formulations SD8 and SD12 prepared with Na2CO3 in 1:2:1 and 1:2:2 V:P:A ratios, and also from formulation SD6 prepared with CaO in 1:2:1 V:P:A ratio). The addition of all alkalizers resulted in higher pHM (Table 1), independently of polymer used, but with considerable differences amongst tested alkalizers. The highest efficiency of Na2CO3 in improving VAL dissolution rate was not correlated with measured pHM, as higher pHM was measured for samples with CaO and MgO. However, the lowest pHM measured for samples with MEG was in accordance with the lowest capacity of this alkalizer to improve VAL dissolution rate. Due to the fastest VAL release achieved, SDs with PVP K25 and CaO or Na2CO3 were further characterized by FT-IR spectroscopy to detect the presence of intermolecular interactions in comparison with binary VAL:PVP SD (SDP) and corresponding physical mixtures (PMs). Shifting and decrease in intensity of VAL absorption band at 1729 cm-1 (carboxyl C=O stretching) and disappearance of peak at 1599 cm-1 (amide C=O stretching) was observed on the spectra of binary VAL:PVP SD compared to PM of equivalent composition, indicating that both C=O groups of VAL can be involved in intermolecular interaction with PVP. The same region of FT-IR spectra was changed in the case of SDs with alkalizer, where peak at 1729 cm-1 disappeared, while peak at 1599 cm-1 was reduced in intensity. Therefore, the same kind of interactions was observed for both binary and ternary SDs, which cannot explain observed faster VAL dissolution rate from ternary SDs with alkalizer. CONCLUSION The addition of alkalizer resulted in significantly improved VAL dissolution rate from SDs prepared with HPMC and PVP, wherein Na2CO3 showed the best performance amongst all tested alkalizers. Since slightly higher pHM was achieved with CaO and MgO, higher efficiency of Na2CO3 can be ascribed to its higher solubility which enables generation of pores in SDs, while release of carbon dioxide facilitates dispersion of particles in the dissolution medium and reduces their tendency towards aggregation. PB - International Association for Pharmaceutical Technology, Mainz, Germany C3 - 12th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, 11-14 May 2021, Vienna, Austria, Virtual meeting T1 - Microenvironmental pH-modified solid dispersions for improving dissolution rate of valsartan SP - 1 EP - 2 UR - https://hdl.handle.net/21.15107/rcub_farfar_5326 ER -
@conference{ author = "Medarević, Đorđe and Dobričić, Vladimir and Krkobabić, Mirjana and Pešić, Nikola and Ibrić, Svetlana", year = "2021", abstract = "INTRODUCTION Formulation of solid dispersions (SDs) with water soluble polymers is one of the most efficient approaches for improving the dissolution rate of poorly soluble drugs. However, this formulation approach might not always be effective in improving the dissolution rate of drugs, especially those with pH-dependent solubility (1). The addition of alkalizers or acidifiers can solve this problem by changing pH in the near vicinity of drug particle surface, (microenvironmental pH) to the range where drug easily dissolves (2). This study evaluated the potential of several alkalizers for improving the dissolution rate of weakly acidic drug valsartan (VAL) from SDs prepared with hydrophilic polymers. EXPERIMENTAL METHODS Materials VAL (Hemofarm a.d., Serbia) was used as a model poorly soluble drug. Hypromellose (HPMC E5, MethocelTM E5 LV premium, Dow Chemicals, USA) and polyvinylpyrrolidone (PVPK25, Kollidon® 25, BASF, Germany) were used as hydrophilic polymers for SDs preparation. Calcium oxide (CaO), magnesium oxide (MgO), sodium carbonate (Na2CO3) and meglumine (MEG) were used as alkalizers in solid dispersions. SDs preparation SDs were prepared in VAL:polymer:alkalizer (V:P:A) weight ratios 1:2:0.5, 1:2:1 and 1:2:2 (Table 1.). Additionally, binary SDs were prepared with VAL and polymer, but without alkalizer. VAL and polymer were dissolved in absolute ethanol on a magnetic stirred followed by dispersion of alkalizer. Ethanol was evaporated from dispersion using rotary evaporator (Büchi Rotavapor®, Büchi Labortechnik AG, Switzerland) at 50 °C. After further vacuum drying, mass was pulverized and sieved through sieve 355 μm. SDs characterization FT-IR spectroscopy (Nicolet iS10, Thermo Scientific, USA) was used to detect the presence of intermolecular interactions between drug, polymer and alkalizer. In vitro drug dissolution testing was performed using a rotating paddle apparatus in 900 ml of 0.1 M HCl as a dissolution medium, due to poor solubility of VAL in this medium. Microenvironmental pH (pHM) was estimated by measuring of pH of concentrated suspension of SD as an indicator of pH near the surface of drug particles. RESULTS AND DISCUSSION Slow and incomplete dissolution of VAL was observed from binary SDs with either PVP or HPMC. The addition of alkalizer resulted in a significantly improved VAL dissolution rate from SDs with both polymers, with faster VAL release from SDs with PVP. Na2CO3 showed the best performance in improving VAL dissolution rate amongst all tested alkalizers. Desired immediate release of VAL (>80% of VAL dissolved after 30 min) was achieved only from formulations SD8 and SD12 prepared with Na2CO3 in 1:2:1 and 1:2:2 V:P:A ratios, and also from formulation SD6 prepared with CaO in 1:2:1 V:P:A ratio). The addition of all alkalizers resulted in higher pHM (Table 1), independently of polymer used, but with considerable differences amongst tested alkalizers. The highest efficiency of Na2CO3 in improving VAL dissolution rate was not correlated with measured pHM, as higher pHM was measured for samples with CaO and MgO. However, the lowest pHM measured for samples with MEG was in accordance with the lowest capacity of this alkalizer to improve VAL dissolution rate. Due to the fastest VAL release achieved, SDs with PVP K25 and CaO or Na2CO3 were further characterized by FT-IR spectroscopy to detect the presence of intermolecular interactions in comparison with binary VAL:PVP SD (SDP) and corresponding physical mixtures (PMs). Shifting and decrease in intensity of VAL absorption band at 1729 cm-1 (carboxyl C=O stretching) and disappearance of peak at 1599 cm-1 (amide C=O stretching) was observed on the spectra of binary VAL:PVP SD compared to PM of equivalent composition, indicating that both C=O groups of VAL can be involved in intermolecular interaction with PVP. The same region of FT-IR spectra was changed in the case of SDs with alkalizer, where peak at 1729 cm-1 disappeared, while peak at 1599 cm-1 was reduced in intensity. Therefore, the same kind of interactions was observed for both binary and ternary SDs, which cannot explain observed faster VAL dissolution rate from ternary SDs with alkalizer. CONCLUSION The addition of alkalizer resulted in significantly improved VAL dissolution rate from SDs prepared with HPMC and PVP, wherein Na2CO3 showed the best performance amongst all tested alkalizers. Since slightly higher pHM was achieved with CaO and MgO, higher efficiency of Na2CO3 can be ascribed to its higher solubility which enables generation of pores in SDs, while release of carbon dioxide facilitates dispersion of particles in the dissolution medium and reduces their tendency towards aggregation.", 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 = "Microenvironmental pH-modified solid dispersions for improving dissolution rate of valsartan", pages = "1-2", url = "https://hdl.handle.net/21.15107/rcub_farfar_5326" }
Medarević, Đ., Dobričić, V., Krkobabić, M., Pešić, N.,& Ibrić, S.. (2021). Microenvironmental pH-modified solid dispersions for improving dissolution rate of valsartan. in 12th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, 11-14 May 2021, Vienna, Austria, Virtual meeting International Association for Pharmaceutical Technology, Mainz, Germany., 1-2. https://hdl.handle.net/21.15107/rcub_farfar_5326
Medarević Đ, Dobričić V, Krkobabić M, Pešić N, Ibrić S. Microenvironmental pH-modified solid dispersions for improving dissolution rate of valsartan. in 12th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, 11-14 May 2021, Vienna, Austria, Virtual meeting. 2021;:1-2. https://hdl.handle.net/21.15107/rcub_farfar_5326 .
Medarević, Đorđe, Dobričić, Vladimir, Krkobabić, Mirjana, Pešić, Nikola, Ibrić, Svetlana, "Microenvironmental pH-modified solid dispersions for improving dissolution rate of valsartan" in 12th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, 11-14 May 2021, Vienna, Austria, Virtual meeting (2021):1-2, https://hdl.handle.net/21.15107/rcub_farfar_5326 .