Solvent free amorphisation for pediatric formulations (minitablets) using mesoporous silica

Fred Monsuur; Yogesh Choudhari; Upendra Reddy; William McCarthy; Ibrar Sadek; Holger Grohganz; Thomas Rades; Korbinian Löbmann

doi:10.1016/j.ijpharm.2016.06.080

Solvent free amorphisation for pediatric formulations (minitablets) using mesoporous silica

Fred Monsuur, Yogesh Choudhari, Upendra Reddy, William McCarthy, Ibrar Sadek, Holger Grohganz, Thomas Rades, Korbinian Löbmann

Abstract

Introduction: Most silica based amorphisation strategies are using organic solvent loading methods. Towards pediatric formulations this is creating concerns. With this in mind the development of a dry amorphisation strategy was the focus of this study. The high internal surface area of mesoporous silica gel is densely crowded with silanol groups, which can provide hydrogen-bonding possibilities with a drug, potentially resulting in amorphisation. Purpose: Amorphous drugs provide an advantage in solubility; however, their low physical stability always remained concern. Additional there was a need to understand the mechanism and variables of dry amorphisation. Method: Ibuprofen (IBU) and Syloid® silica at different ratios were co-milled at variable milling times between 1 and 90 min. The interaction with; and amorphisation of IBU; on Syloid® silica was analyzed using SEM, FTIR, DSC and XRD. The co-milled powder was compressed into minitablets using moisture activated dry granulation (MADG). Drug release studies were conducted. Results: Ball milling as dry loading technique resulted within 30 min; in the conversion of crystalline IBU into an amorphous form in the presence of Syloid® silica. It was found that the amorphisation is a result of milling equilibrium, electrostatic interaction and hydrogen bonding between silanol groups of Syloid® silica and IBU. The extent of amorphisation was influenced by milling time, milling frequency and quantity of mesoporous silica. As a consequence, the amorphous IBU-silica samples showed improved solubility over the unmilled drug and showed physical stability of the amorphous IBU. Milling IBU alone did not result in an amorphous product; hence its dissolution did not show any improvement over unmilled drug. Conclusion: Dry amorphisation of silica based amorphous drug formulations does not involve organic solvents and is thereby acceptable for pediatric formulations, cost effective and time saving while increasing oral bioavailability of crystalline & poorly water soluble drugs.

Original language	English
Journal	International Journal of Pharmaceutics
Volume	511
Issue number	2
Pages (from-to)	1135-1136
ISSN	0378-5173
DOIs	https://doi.org/10.1016/j.ijpharm.2016.06.080
Publication status	Published - 25 Sept 2016

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10.1016/j.ijpharm.2016.06.080

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@article{e5269dd673934e71b9c955afe80b1813,

title = "Solvent free amorphisation for pediatric formulations (minitablets) using mesoporous silica",

abstract = "Introduction: Most silica based amorphisation strategies are using organic solvent loading methods. Towards pediatric formulations this is creating concerns. With this in mind the development of a dry amorphisation strategy was the focus of this study. The high internal surface area of mesoporous silica gel is densely crowded with silanol groups, which can provide hydrogen-bonding possibilities with a drug, potentially resulting in amorphisation. Purpose: Amorphous drugs provide an advantage in solubility; however, their low physical stability always remained concern. Additional there was a need to understand the mechanism and variables of dry amorphisation. Method: Ibuprofen (IBU) and Syloid{\textregistered} silica at different ratios were co-milled at variable milling times between 1 and 90 min. The interaction with; and amorphisation of IBU; on Syloid{\textregistered} silica was analyzed using SEM, FTIR, DSC and XRD. The co-milled powder was compressed into minitablets using moisture activated dry granulation (MADG). Drug release studies were conducted. Results: Ball milling as dry loading technique resulted within 30 min; in the conversion of crystalline IBU into an amorphous form in the presence of Syloid{\textregistered} silica. It was found that the amorphisation is a result of milling equilibrium, electrostatic interaction and hydrogen bonding between silanol groups of Syloid{\textregistered} silica and IBU. The extent of amorphisation was influenced by milling time, milling frequency and quantity of mesoporous silica. As a consequence, the amorphous IBU-silica samples showed improved solubility over the unmilled drug and showed physical stability of the amorphous IBU. Milling IBU alone did not result in an amorphous product; hence its dissolution did not show any improvement over unmilled drug. Conclusion: Dry amorphisation of silica based amorphous drug formulations does not involve organic solvents and is thereby acceptable for pediatric formulations, cost effective and time saving while increasing oral bioavailability of crystalline & poorly water soluble drugs.",

author = "Fred Monsuur and Yogesh Choudhari and Upendra Reddy and William McCarthy and Ibrar Sadek and Holger Grohganz and Thomas Rades and Korbinian L{\"o}bmann",

year = "2016",

month = sep,

day = "25",

doi = "10.1016/j.ijpharm.2016.06.080",

language = "English",

volume = "511",

pages = "1135--1136",

journal = "International Journal of Pharmaceutics",

issn = "0378-5173",

publisher = "Elsevier",

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TY - ABST

T1 - Solvent free amorphisation for pediatric formulations (minitablets) using mesoporous silica

AU - Monsuur, Fred

AU - Choudhari, Yogesh

AU - Reddy, Upendra

AU - McCarthy, William

AU - Sadek, Ibrar

AU - Grohganz, Holger

AU - Rades, Thomas

AU - Löbmann, Korbinian

PY - 2016/9/25

Y1 - 2016/9/25

N2 - Introduction: Most silica based amorphisation strategies are using organic solvent loading methods. Towards pediatric formulations this is creating concerns. With this in mind the development of a dry amorphisation strategy was the focus of this study. The high internal surface area of mesoporous silica gel is densely crowded with silanol groups, which can provide hydrogen-bonding possibilities with a drug, potentially resulting in amorphisation. Purpose: Amorphous drugs provide an advantage in solubility; however, their low physical stability always remained concern. Additional there was a need to understand the mechanism and variables of dry amorphisation. Method: Ibuprofen (IBU) and Syloid® silica at different ratios were co-milled at variable milling times between 1 and 90 min. The interaction with; and amorphisation of IBU; on Syloid® silica was analyzed using SEM, FTIR, DSC and XRD. The co-milled powder was compressed into minitablets using moisture activated dry granulation (MADG). Drug release studies were conducted. Results: Ball milling as dry loading technique resulted within 30 min; in the conversion of crystalline IBU into an amorphous form in the presence of Syloid® silica. It was found that the amorphisation is a result of milling equilibrium, electrostatic interaction and hydrogen bonding between silanol groups of Syloid® silica and IBU. The extent of amorphisation was influenced by milling time, milling frequency and quantity of mesoporous silica. As a consequence, the amorphous IBU-silica samples showed improved solubility over the unmilled drug and showed physical stability of the amorphous IBU. Milling IBU alone did not result in an amorphous product; hence its dissolution did not show any improvement over unmilled drug. Conclusion: Dry amorphisation of silica based amorphous drug formulations does not involve organic solvents and is thereby acceptable for pediatric formulations, cost effective and time saving while increasing oral bioavailability of crystalline & poorly water soluble drugs.

AB - Introduction: Most silica based amorphisation strategies are using organic solvent loading methods. Towards pediatric formulations this is creating concerns. With this in mind the development of a dry amorphisation strategy was the focus of this study. The high internal surface area of mesoporous silica gel is densely crowded with silanol groups, which can provide hydrogen-bonding possibilities with a drug, potentially resulting in amorphisation. Purpose: Amorphous drugs provide an advantage in solubility; however, their low physical stability always remained concern. Additional there was a need to understand the mechanism and variables of dry amorphisation. Method: Ibuprofen (IBU) and Syloid® silica at different ratios were co-milled at variable milling times between 1 and 90 min. The interaction with; and amorphisation of IBU; on Syloid® silica was analyzed using SEM, FTIR, DSC and XRD. The co-milled powder was compressed into minitablets using moisture activated dry granulation (MADG). Drug release studies were conducted. Results: Ball milling as dry loading technique resulted within 30 min; in the conversion of crystalline IBU into an amorphous form in the presence of Syloid® silica. It was found that the amorphisation is a result of milling equilibrium, electrostatic interaction and hydrogen bonding between silanol groups of Syloid® silica and IBU. The extent of amorphisation was influenced by milling time, milling frequency and quantity of mesoporous silica. As a consequence, the amorphous IBU-silica samples showed improved solubility over the unmilled drug and showed physical stability of the amorphous IBU. Milling IBU alone did not result in an amorphous product; hence its dissolution did not show any improvement over unmilled drug. Conclusion: Dry amorphisation of silica based amorphous drug formulations does not involve organic solvents and is thereby acceptable for pediatric formulations, cost effective and time saving while increasing oral bioavailability of crystalline & poorly water soluble drugs.

U2 - 10.1016/j.ijpharm.2016.06.080

DO - 10.1016/j.ijpharm.2016.06.080

M3 - Conference abstract in journal

SN - 0378-5173

VL - 511

SP - 1135

EP - 1136

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

IS - 2

ER -