title: Characterization and evaluation of multi-component crystals of hydrochlorothiazide.
abstract: OBJECTIVE
  The present work aims at improving the physicochemical properties of hydrochlorothiazide, a poorly water soluble antihypertensive drug by preparing its multi-component crystals with nicotinic acid (HCT-NA) and 2-picolinic acid (HCT-PIC).
  
  
  METHODS
  The crystals prepared by solution crystallization were investigated by thermoanalytical techniques. The crystal structures of HCT-NA (1) and HCT-PIC (2) were determined by the single crystal X-ray diffraction and were assessed for their aqueous solubility, antihypertensive activity and acute toxicity in rats.
  
  
  RESULTS
  Both 1 and 2 crystallized in the orthorhombic space group P212121 and formation of salts were confirmed. The solubility profiles of 1 and 2 in basic media showed a maximum release of 2.5 mg/ml and 1.9 mg/ml, respectively, in comparison to the drug (0.82 mg/ml). The in-vivo antihypertensive activity of 1 in deoxycorticosterone acetate salt induced hypertensive rats showed 1.5 fold improvement. No increase in the signs of toxicity were revealed in rats during the acute toxicity studies even at doses of 2,000 mg/kg by body weight in comparison to the free drug. Histopathological findings supported the safety of these multi-component crystals.
  
  
  CONCLUSIONS
  The new solid phases exhibit potential to be explored for the oral drug delivery of HCT with improved solubility and therapeutic outcome.
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India, renukchadha@rediffmail.com.
authors.forename: Renu
authors.initials: R
authors.lastname: Chadha
authors.forename: Swati
authors.initials: S
authors.lastname: Bhandari
authors.forename: Sadhika
authors.initials: S
authors.lastname: Khullar
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Mandal
authors.forename: D V S
authors.initials: DV
authors.lastname: Jain
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000627:therapeutic use* / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects; D003460:Crystallization / Q000379:methods; D005260:Female; D006852:Hydrochlorothiazide / Q000737:chemistry* / Q000627:therapeutic use* / Q000633:toxicity; D006973:Hypertension / Q000188:drug therapy*; D009525:Niacin / Q000737:chemistry; D010848:Picolinic Acids / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D014961:X-Ray Diffraction
chemical_list: D000959:Antihypertensive Agents; D010848:Picolinic Acids; D006852:Hydrochlorothiazide; D009525:Niacin
references.citation: Mol Pharm. 2007 May-Jun;4(3):323-38
references.pmid: 17461597
references.citation: Molecules. 2011 May 27;16(6):4482-99
references.pmid: 21623317
references.citation: Adv Drug Deliv Rev. 2004 Feb 23;56(3):275-300
references.pmid: 14962582
references.citation: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
references.pmid: 11259830
references.citation: Pharm Res. 1998 Nov;15(11):1787-91
references.pmid: 9834004
references.citation: Pharm Dev Technol. 2013 Mar-Apr;18(2):504-14
references.pmid: 23061933
references.citation: Acta Crystallogr A. 2008 Jan;64(Pt 1):112-22
references.pmid: 18156677
references.citation: Pharm Res. 2000 Apr;17(4):397-404
references.pmid: 10870982
references.citation: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):75-87
references.pmid: 11259834
references.citation: Expert Opin Drug Deliv. 2009 Apr;6(4):333-41
references.pmid: 19348603
references.citation: Pharm Res. 1998 Jan;15(1):11-22
references.pmid: 9487541
references.citation: J Pharm Sci. 2006 Mar;95(3):499-516
references.pmid: 16444755