FABRICATION AND CHARACTERIZATION OF POSACONAZOLE

LOADED GEL FOR THE MANAGEMENT OF ONYCHOMYCOSIS

FINAL THESIS PRESENTATION

OF
MASTER OF PHARMACY
(PHARMACEUTICS)
BY
NAVDEEP SINGH
Regd No. UIP/F-048

SUPERVISOR CO- SUPERVISOR

DR. HONEY DR. VINEY CHAWLA
Assistant Professor Professor and Principal
UIPSR, BFUHS, Faridkot UIPSR, BFUHS, Faridkot

UNIVERSITY INSTITUTE OF PHARMACEUTICAL SCIENCES AND RESEARCH,

BABA FARID UNIVERSITY OF HEALTH SCIENCES, FARIDKOT
Contents

 Introduction

 Rationale of the Study

 Aims of the Study

 Plan of the Work

 Materials and Methods

 Results and Discussion

 Summary & Conclusion

 Achievements
Introduction
• Fungal infections can be superficial or systemic, affecting skin or internal organs. Especially in
those with weakened immune systems.Widespread use of immunosuppressive drugs,
chemotherapy and due to diseases like diabeties, HIV, Tuberculosis and COVID-19 has contributed
to an increased incidence of fungal infections, with drug resistance being a significant concern.

• Globally, over 13 million infections and 1.5 million deaths annually, Candida albicans affects
over 1.5 million people annually.

• Candida albican is a common yeast-like fungus that can cause infections in humans. While
Candida albicans is part of the normal microbiota of the skin, mouth, intestines, and other mucous
membranes, it can lead to infection when overgrowth occurs, often due to weakened immune
systems.
• Antifungals are medications designed to treat fungal infections by inhibiting the Synthesis of
Ergosterol and Peptidoglycan, with FDA approved classes i.e. Polyenes, Azoles, Allylamines, and
Echinocandins. Which are classified as Biopharmaceutics Classification System (BCS) Class II
drugs, which have low solubility but high permeability.

• Among the antifungal azoles, drug therapies such as Posaconazole face challenges with poor
aqueous solubility (<1 μg/mL) (0.0659 mg/mL), limiting their efficacy and bioavailability.

• To address solubility issues, solid dispersion play a crucial role in overcoming challenges related to
poor solubility and dose-related toxicity in antifungal drug delivery.
Rationale of the Study:
• Posaconazole, a BCS Class II FDA approved drug in 2006, exhibit poor aqueous solubility at (<1 μg/mL) and a log
P value of 5.5, leading to low bioavailability. Due to its poor solubility and bioavailability, high dose is required to
produce therapeutic effect. Thus current oral and parentral formulations of Posaconazole posses some serious side
effects.

• Currently, no solid dispersion based gel formulation of posaconazole is available, primarily used treatment of
superficial fungal infections like candida albicans based Onychomycosis.
Limitations in marketed formulations:
• Drug Interactions:They inhibit the metabolism of several drugs by inhibiting cytochrome P450 enzymes.
• Hepatotoxicity:These formulations are hepatotoxic.
• QT Prolongation:They can prolong the QT interval, increasing the risk of cardiac arrhythmias.
• It was necessary to make the topical formulations to overcome these systemic side effects of posaconazole.
 Drug Characteristics
Class Pharmacokinetics Dosage Mechanism of Action

Posaconazole, a BCS Posaconazole has long Oral 40mg-100mg Posaconazole functions

Class II drug, is half life (approx. 35 IV- 300mg by inhibiting ergosterol
characterized by low hours) and is primarily synthesis through
aqueous solubility, metabolized by the liver blocking lanosterol 14α-
which can limit through demethylase,
dissolution and glucuronidation.Its compromising fungal
absorption, but it also absorption is enhanced cell membrane integrity,
exhibits high by food intake,and it is
permeability, facilitating excreted mainly via the
effective absorption in feces.
topical formulations.
AIM:

• To formulate the solid dispersion based Posaconazole Loaded Gel For The Management Of
Onychomycosis.
• To characterize Posaconazole SD gel formulations by assessing the parameters such as solubility,
permeability, bioavailability, and therapeutic efficacy through in vitro Studies.
PLAN OF WORK:
• Pre-formulation studies for Posaconazole to investigate the morphology, physiochemical
characterization and drug excipient compatibility studies by employing FTIR,DSC studies.
• Fabrication of solid dispersions formulations of Posaconazole to enhance solubility and
bioavailability.
• Characterization of solid dispersions by FTIR and XRD for Solublity and Stablity.
• Incorporating solid dispersion into a gel and is evaluated for parameters like drug release, stability,
and viscosity to improve therapeutic efficacy.
• Antifungal susceptibility assays were conducted to evaluate the drug's efficacy, revealing
promising results against candida albicans based Onychomycosis.
• Accelerated stability studies were carried out for a period of 30 days at 4±1°C as per literature
studies.
 MATERIALS AND METHODS:
API Polymer Excipients Posaconazole and biocompatible polymers (e.g., PVP K30,
1. Posaconazole 1. PVP-K30 (poly 1. Methanol PEG 4000, Sorbitol) were chosen for solid dispersion
vinyl 2. phosphate formulation.
pyrrolidone) buffer
2. PEG 4000 3. Glycerin Posaconazole -loaded solid dispersions were prepared via
3. Sorbitol 4. Methylparabe Kneading Method, incorporating the drug into solid
4. Carbopol n hydrophilic carrier.
934(Gelling
Gel base was prepared by soaking 1% w/v Carbopol 934 in
Agent)
phosphate buffer and neutralize with sodium hydroxide
(NaOH)
Solid dispersion was incorporated and stirred well. Necessary
amount of Glycerin and Methylparaben was added by
continuous stirring until a homogeneous gel was obtained
and stored in suitable container.
RESULTS AND DISCUSSION
 Preformulation Studies :

Organoleptic Properties Melting Point

Parameters Reference Observed Parameter Reference Observed
Nature Solid, crystalline. Solid, Melting 170-178.6°C 176.34°C.
crystalline. Point

Color White White

The Melting point determination indicates the purity of
Odor Odorless. Odorless. API.Melting point was determined by capillary tube
method and was noted 176.34°C.
similar as given in literature.
• Standardization of Posaconazole by UV

• UV spectrum of Posaconazole sample showed Maximum absorption at 264

nm which was consistent with the reference value.
• FTIR spectrum of Posaconazole:

• Based on the characteristic peaks for C-H aromatic ring vibrations at 3427.2 cm⁻¹ and 2883.1 cm⁻¹
(C-H alkyl), C=O 1692.2 cm⁻¹, C=N 1397.8 cm⁻¹ observed in the FTIR analysis, it was concluded
that the luliconazole drug sample conformed to the standard spectrum specifications reported in the
literature.
• Differential scanning Calorimetry:

• DSC thermogram showed a sharp endotherm(indicating Amorphous state) at 176.34°C.

• Consistent with the standard melting temperature, indicating sample purity.
• XRD spectra of Posaconazole sample

• Diffractogram of Posaconazole which exhibited sharp intense peaks that might be attributed to
different crystalline nature and arrangement of molecules respectively at 7.00◦, 7.70◦, 9.00◦, 9.97◦,
11.72◦, 14.45◦, 16.02◦, 17.88◦, 19.69◦, 20.93◦, 22.35◦, 23.26◦, 24.46◦, 25.56◦, 27.71◦, 29.22◦,
31.29◦, 32.90◦, 33.86◦, 36.09◦, 38.36◦, 39.74◦, 43.72◦, 45.89◦ and 49.25◦. The XRD data of drug
sample was observed to be are in good agreement with those of reported literature values.
• UV spectrophotometric method for the estimation of Posaconazole

Calibration curve of PCZ in methanol Calibration curve of PCZ in phosphatebuffer

The spectrophotometer was carried out in methanol and phosphate at wavelenght 264 nm and the
drug was found in the concentration of 1-30µg/ml in methanol, 1-15µg/ml phosphate buffer. Linear
calibration curve obtained thus Follows Beer-Lambert's Law.
Physical and Chemical Stability Studies
• Table : Physical stability during storage

• The stored physical mixtures of drug and solid lipids showed no significant changes in
physical state or organoleptic properties, confirming compatibility with Posaconazole over
the storage period.
Drug-Excipient Interaction Studies:

• FTIR Spectrum of physical mixtures:

FTIR Spectrum of physical mixtures A) PCZ and PVPK30 B) PCZ and PEG 4000 C) PCZ and sorbitol
Characteristic PCZ peaks were retained in all mixtures. Confirming compatibility between
PCZ and the excipients. No significant Chemical interactions.
• X-Ray Diffraction (XRD) Analysis of API and Excipients:

XRD diffractogram of physical mixtures A) PCZ and PVP K30 B) PCZ and PEG C) PCZ and Sorbitol.

• Sharp, intense peaks of PCZ were retained in all mixtures, confirming crystalline
nature.
• Conclusion: PCZ remained stable in its crystalline form, indicating no significant
interaction with excipients.
Physicochemical Characterization of Solid
Dispersion:
• FTIR Spectrum of solid dispersion Batches:

FTIR Spectrum of solid dispersions A) PCZ and PVPK30 B) PCZ and PEG 4000 C) PCZ and
sorbitol.
• . No significant peak disappearance or changes, confirming no chemical interaction between
PCZ and excipients
• XRD Studies of Solid Dispersion:

XRD diffractogram of solid dispersions (SDs) A) PCZ and PVP-K30 B) PCZ and sorbitol C) PCZ and
PEG 4000.

• PCZ-SD with PVP-K30 (1:2) showed reduced diffraction peak intensity, indicating
Amorphous structure.Thus molecular dispersion achieved.
• Slight decrease in crystallinity observed for PCZ-SD with Sorbitol and PEG-4000.
 Percentage Yield and % Drug Content
100.0

75.0

50.0

25.0
PCKSD11 PCKSD12 PCKSD13 PCPSD11 PCPSD12 PCPSD13 PCSSD11 PCSSD12 PCSSD13

% Drug Content % Yield

Figure 8: Percentage Yield and Percentage Drug Content of aceclofenac formulations

The drug content and yield across all solid dispersion batches demonstrated consistently
high values, indicating that variations in the drug/polymer ratio did not significantly affect
the formulation outcome, largely due to the high solubility of the drug in the polymeric
matrix.
Formulation of SD Gels and Their Physicochemical Characterization
Table 4: Physical Appearance of SD Gel batches
Spreadabili
ty
Viscosi
Batch Homogenei Consisten (cm)
pH ty
Code ty cy
(cps)

PCKSD1 5.71±0.
√ √ 65498 7.1±1.2
1G 21

PCKSD1 5.83±0.
√ √ 72319 6.8±0.9
2G 29

The final optimized SD gel formulations (PCKSD11G and PCKSD12G) exhibited appropriate
physicochemical properties, including homogeneity, consistency, suitable pH, and spreadability,
making them ideal for topical application.
 Drug release, kinetic models and mechanism
Table 9: Correlation coefficients (R2) and release exponent (n) values obtained from the different
kinetic models for finally optimized aceclofenac-SD gels

PCKSD11G PCKSD12G
Kinetic Model
R2 n R2 n

Zero order 0.7136 6.2 0.7443 6.23

First order 0.9168 -0.1001 0.982 -0.1577

Higuchi 0.6428 37.627 0.5334 41.086

Korsemeyer- 0.8193 0.520 0.9052 0.456

Peppas

The kinetic evaluation of optimized SD gel batches (PCKSD11G and PCKSD12G) indicated that
the drug release followed first-order kinetics, with a predominantly diffusion-controlled
mechanism, confirmed by release exponent (n) values <0.5.
 In vitro drug release studies

Comparative % cumulative in vitro drug release

•SD gel formulations (PCKSD11G and PCKSD12G) showed significantly higher drug release profiles
compared to plain PCZ and PMF formulations.
Both Gel formulations exhibited approximately 90% cumulative drug release, suggesting more complete
and efficient drug release.
 Antifungal Susceptibility Assay

Antifungal susceptibility assay

•The minimum inhibitory concentration (MIC) of PCZ against Candida albicans was noted from
the literature at ≤0.5 µg/mL with inhibition levels exceeding 90% after 24 hours.
Treatment and control groups are cultured with Candida albicans to compare gel batches containing
Posaconazole with a marketed Posaconazole formulation for antifungal efficacy.
•PMF: inhibition diameter 21.17 ± 1.90 mm
•PCKSD11G (PCZ-SD gel batch): inhibition diameter 26.37 ± 0.91 mm
•PCKSD12G (PCZ-SD gel batch): inhibition diameter 32.07 ± 1.90 mm
 Stability studies

% Mean Drug content ±S.D. (n=3)

Batch
At After 1 After 2 After 3
0 month month months months

PCKSD11G 97.17±0.33 96.8±1.21 93.5±0.69 95.8±1.26

PCKSD12G 96.44±0.40 95.7±0.85 98.8±0.57 96.7±1.74

The stability study of the optimized SD gel formulations (PCKSD11G and PCKSD12G) confirmed
that no significant physical or chemical variations were observed, indicating that the gels remained
stable under accelerated storage conditions for 3 months.
 Summary
• Preformulartion studies on PCK showed melting point 176.34°C, endothermic sharp peak at
176.34°C in DSC studies and characterstic absorption peaks at 3427.2 cm-1 and 2883.1 cm-1 for the
presence of groups such as C-H aromatic and C-H alkyl in FTIR spectral studies respectivily .
Further X-Ray diffraction data also recived for purity of drug similar to DSC and FTIR studies.

• For the quantative analysis of PCZ as an analytical method based on UV spectroscopy in methanol
and phosphate buffer respectively established linearly and obeyed Beer lambert law.

• Drug exciepient compatibilty was checked by using FTIR of PCK with various formulations
exciepients confirmed that the PCK maintained its chemical integirity in presence of chosen
polymers and exciepients.
Thanks