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ORIGINAL/BRIEF
Year : 2012  |  Volume : 4  |  Issue : 5  |  Page : 106-107  

Preparation, characterization and in vitro dissolution study of Nitrazepam: Cyclodextrin inclusion complex


Department of Pharmaceutics and Pharmaceutics Technology, S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Kherva, Gujarat, India

Date of Web Publication21-Mar-2012

Correspondence Address:
J S Patel
Department of Pharmaceutics and Pharmaceutics Technology, S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Kherva, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-7406.94158

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   Abstract 

The objectives of this research were to prepare and characterize inclusion complexes of Nitrazepam with Hydroxypropyl-β-cyclodextrin (HPβCD) and Sulfobutyl ether β-cyclodextrin (SBEβCD) to study the effect of complexation on the dissolution rate of Nitrazepam, a water-insoluble drug. The phase solubility profile of Nitrazepam with Hydroxypropyl- β-cyclodextrin and Sulfobutyl ether β-cyclodextrin was an AP-type, indicating the formation of 2:1 stoichiometric inclusion complexes. Gibbs free energy values were all negative, indicating the spontaneous nature Nitrazepam solubilization and their value decreased with increase in the cyclodextrin concentration, demonstrating that the reaction conditions became more favorable as the concentration of cyclodextrins increased. Complexes of Nitrazepam were prepared with cyclodextrin using various methods such as physical mixing, kneading, spray-drying and lyophilization. The complexes were characterized by Differential scanning calorimetry, Fourier-transform infrared, scanning electron microscopy and powder X-ray diffraction studies. These studies indicated that a complex prepared by lyophilization had successful inclusion of the Nitrazepam molecule into the cyclodextrin cavity. Complexation resulted in a marked improvement in the solubility and wettability of Nitrazepam. Among all the samples, a complex prepared with Sulfobutyl ether β-cyclodextrin by lyophilization had the greatest improvement in the in vitro rate of Nitrazepam dissolution. The mean dissolution time for Nitrazepam decreased significantly after preparing complexes. The similarity factor indicated a significant difference between the release profiles of Nitrazepam from complexes, physical mixtures and plain Nitrazepam. To conclude that, the tablets containing complexes prepared with Cyclodextrins had significant improvement in the release profile of Nitrazepam as compared to tablets containing Nitrazepam without cyclodextrin.

Keywords: Inclusion complexes, hydroxypropyl-β-cyclodextrin, sulfobutyl ether β-cyclodextrin, nizatriptam


How to cite this article:
Patel J S, Patel R P. Preparation, characterization and in vitro dissolution study of Nitrazepam: Cyclodextrin inclusion complex. J Pharm Bioall Sci 2012;4, Suppl S1:106-7

How to cite this URL:
Patel J S, Patel R P. Preparation, characterization and in vitro dissolution study of Nitrazepam: Cyclodextrin inclusion complex. J Pharm Bioall Sci [serial online] 2012 [cited 2019 Nov 12];4, Suppl S1:106-7. Available from: http://www.jpbsonline.org/text.asp?2012/4/5/106/94158

Nitrazepam (NTR), a potent benzodiazepine, is used for the short-term relief of symptoms of anxiety or anxiety associated with depression. Because of its poor water solubility and extensive metabolism in the liver into pharmacologically inactive glucuronides, NTR oral therapy is associated with a slow onset of drug action. Generally, compounds with very low aqueous solubility are considered to have dissolution rate-limited absorption and hence poor absorption, distribution, and target organ delivery.

In present investigation, a fast- dissolving form of the compound with a high level of aqueous solubility is desirable for rapid absorption of the drug during oral benzodiazepine therapy. Complexation of such drugs with cyclodextrin (CDs) represents one way to achieve that goal.

Materials and Methods

Stoichiometric ratio was determined by phase solubility method and complex was prepared using kneading, spray drying and lyophilization. The complexes were characterized by differential scanning calorimetry, fourier-transform infrared spectroscopy, scanning electron microscopy, and powder X-ray diffraction studies, drug content, wettability, dissolution and parameter for tabletting efficiency.

Results and Discussion

Phase solubility analysis has been among the preliminary requirements for optimizing the development of inclusion complexes of drugs as it permits the evaluation of the affinity between a CD and drug molecule in water. Increased solubility may be due to improved dissolution of NTR particles in water due to the presence of CDs. The solubility of NTR increased by 218-fold at 37°C and 158-fold at 25°C and121-fold at 37°C and 72-fold at 25°C at a 200 mM concentration of SBE-β-CD and HP β-CD respectively. This curve indicated an increase in the solubility of NTR with an increase in the concentration of the CD in water. Increasing the amount of the CD increased the amount of NTR entering the water, improving the aqueous solubility of NTR.

Gibbs free energy values were all negative, indicating the spontaneous nature Nitrazepam solubilization and their value decreased with increase in the cyclodextrin concentration, demonstrating that the reaction conditions became more favorable as the concentration of cyclodextrin increased.

Drug content of HPβCD and SBEβCD formulations was found to be 85% and 96%, respectively. The results of DSC and FTIR study showed that Nitrazepam was compatible with both cyclodextrins and complex formed by spray drying and lyophilization is best. The results of wettability, dissolurion and in vitro release study were shown in [Figure 1], [Figure 2].
Figure 1: (a) Wettability (b) Drug release

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Figure 2:

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Conclusion

Solubility studies revealed a significant increase in the aqueous solubility of NTR with an increase in the concentration of HP-β-CD and SBE-β-CD. The maximum concentration of HP- β -CD and SBE-β-CD studied (200 mM at 37°C) resulted in 121-fold and 218-fold improvement in the saturation solubility of Nitrazepam. An inclusion complex of Nitrazepam with HP-β-CD and SBE-β-CD at a molar ratio of 2:1 was successfully prepared by kneading, spray-drying, and lyophilization. This was confirmed by DSC, FTIR, SEM, and XRD studies. The greatest improvement in solubility and in vitro drug release was observed with an inclusion complex prepared with SBE-β-CD by lyophilization. The solubility and in vitro drug release of a physical mixture improved to a lesser degree than did that of complexes prepared by kneading, spray-drying, and lyophilization. These finding are extremely important from commercial point of view as the prepared complex remedies the drawback of NTR's poor dissolution profile. [1]

 
   References Top

1.Singh R. Characterization of cyclodextrin inclusion complexes-A review. Journal of Pharmaceutical Science and technology 2010; 2(3): 171-183.  Back to cited text no. 1
    


    Figures

  [Figure 1], [Figure 2]


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