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Molecules
Volume 21
Issue 6
10.3390/molecules21060719
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Article

Hydrogen Bonding: Between Strengthening the Crystal Packing and Improving Solubility of Three Haloperidol Derivatives

by
Hardeep Saluja
1,
Ahmed Mehanna
2,
Riccardo Panicucci
3,† and
Eman Atef
2,4,*,†
1
Department of Pharmaceutical Sciences, Southwestern Oklahoma State University, 100 Campus Drive, Weatherford, OK 73096-3098, USA
2
Department of Pharmaceutical Sciences, MCPHS-University-Boston, 179 Longwood Ave, Boston, MA 02115, USA
3
WuXi AppTec, Cambridge, MA 02142, USA
4
College of Pharmacy, California Northstate University, 9700 W Taron Drive, Elk Grove, CA 95757, USA
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Academic Editor: Sohrab Rohani
Molecules 2016, 21(6), 719; https://doi.org/10.3390/molecules21060719
Received: 16 January 2016 / Revised: 9 May 2016 / Accepted: 21 May 2016 / Published: 1 June 2016
(This article belongs to the Section Medicinal Chemistry)
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Abstract

The purpose of this study is to confirm the impact of polar functional groups on inter and intra-molecular hydrogen bonding in haloperidol (HP) and droperidol (DP) and, hence, their effects on dissolution using a new approach. To confirm our theory, a new molecule: deshydroxy-haloperidol (DHP) was designed and its synthesis was requested from a contract laboratory. The molecule was then studied and compared to DP and HP. Unlike DHP, both the HP and DP molecules have hydrogen donor groups, therefore, DHP was used to confirm the relative effects of the hydrogen donor group on solubility and crystal packing. The solid dispersions of the three structurally related molecules: HP, DP, and DHP were prepared using PVPK30, and characterized using XRPD and IR. A comparative dissolution study was carried out in aqueous medium. The absence of a hydrogen bonding donor group in DHP resulted in an unexpected increase in its aqueous solubility and dissolution rate from solid dispersion, which is attributed to weaker crystal pack. The increased dissolution rate of HP and DP from solid dispersions is attributed to drug-polymer hydrogen bonding that interferes with the drug-drug intermolecular hydrogen bonding and provides thermodynamic stability of the dispersed drug molecules. The drug-drug intermolecular hydrogen bond is the driving force for precipitation and crystal packing. View Full-Text
Keywords: drug crystal packing; hydrogen bonding; solid dispersion; haloperidol-related compounds; molecular interaction; hydrophobic interaction; droperidol; deshydroxyhaloperidol drug crystal packing; hydrogen bonding; solid dispersion; haloperidol-related compounds; molecular interaction; hydrophobic interaction; droperidol; deshydroxyhaloperidol
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MDPI and ACS Style

Saluja, H.; Mehanna, A.; Panicucci, R.; Atef, E. Hydrogen Bonding: Between Strengthening the Crystal Packing and Improving Solubility of Three Haloperidol Derivatives. Molecules 2016, 21, 719. https://doi.org/10.3390/molecules21060719

AMA Style

Saluja H, Mehanna A, Panicucci R, Atef E. Hydrogen Bonding: Between Strengthening the Crystal Packing and Improving Solubility of Three Haloperidol Derivatives. Molecules. 2016; 21(6):719. https://doi.org/10.3390/molecules21060719

Chicago/Turabian Style

Saluja, Hardeep, Ahmed Mehanna, Riccardo Panicucci, and Eman Atef. 2016. "Hydrogen Bonding: Between Strengthening the Crystal Packing and Improving Solubility of Three Haloperidol Derivatives" Molecules 21, no. 6: 719. https://doi.org/10.3390/molecules21060719

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