| الملخص | Abstract
This work has been carried out to develop national drug product contains (2%)ketoconazolas Suspension, it is indicated in the treatment of fungal skin and nail infections and chronic mucocutaneous candidiasis that cannot be treated topically.
Several formulations were prepared using different suspension bases, preservatives and suspending agent. Selection of best formula relied solelyon physicochemical testing of sample.
Stability study was conducted on the product for 6 months at different temperatures to determine the expiration date and the best storage conditions.
Antifungal ketoconazolsuspension of good homogeneity and softness solution was obtained.The expiry date calculated to be not less than (2) years.
Keywords :Ketoconazole, antifungal,oral suspension .
Introduction
Ketoconazole is an imidazole antifungal that interferes with ergo sterol synthesis and therefore alters the permeability of the cell membrane of sensitive fungi. It is reported to be fungi static at concentration achieved clinically. [1]
Effective pharmaceutical ingredient must be formulated in a suitable dosage form to enable the patient to get active and safe drug with good features.
ketoconazolehas activity against some gram positive bacteria and some antiprotozoalinfection ,including acanthamoeba infections and leishmaniasis.It has also been used in the management of acute respiratory distress syndrome, hypercalacaemia, and certain endocrine disorders and malignancies [2]
In infants and children,ketoconazole may be used topically for the treatment of fungal skin infections similarly to in adults. It may also be used orally in children for the treatment of fungal skin and nail infections
and chronic mucocutaneous candidiasis that cannot be treated topically; oral use should be restricted to situations where other anti-fungal cannot be used due to resistance or intolerance.
Ketoconazole is a white or almost white powder, practically insoluble in water, freely soluble in methylene chloride, soluble in methanol, sparingly soluble in ethanol (96 per cent). [3]
Asuspension containing ketoconazole (2%) is a generic drug not manufactured in the Iraqi factories; therefore the aim of study is a necessity to have an Iraqi formula for this dosage form with its stability study compatible with specification of British pharmacopeia. This study is considered one of the important documents for the purposes of registration in the ministry of health.
Materials and methods
In suitable pyrex beaker transfer the following materials, deionizedwater, xanthan gum,sorbitol (70%),sodium citrate,citric acid anhydrous, then mix well for (30 min) or until clear solution is formed. Inanother pyrex beaker dissolve methyl paraben,propylparaben in the stated amount of propylene glycol, add to above mixture with continuous mixing , add the accurately weight of ketoconazole to above mixture, mix and homogenize for (30 min). The volume was adjusted with distilled water, and then fill in (100 ml) amber glass bottle.
Method of analysis:
1. Assaymethod:united state pharmacopeia (30) with modified
2. Composition : Each (1 ml) Suspension contains (20) mg ketoconazole
3. Assay limit: (90 - 110) %
4. pH.limit : (4-6.5)
5. H.P.L.C. conditions:
A. Colum: C18 25cm
B. Wave length: 232 nm
C. Flow rate: 1.5ml/min
D. Solvent: methanol
E. Mobile phase: 70% acetonitrile in 20M NaHPO4
Containing 0.2%v/v diethyl amine at pH = 4
F. Retention time: 7.5 min.
Buffer preparation:Weight 1.4196gm of Na2HPO4 then dissolve to 500ml distilled water, add 1ml of diethyl amine Adjust pH to 4
50% methanol :Take 50 ml of methanol up to 100 ml of D.W
Assay:
Standard: Weigh accurately (200mg) ofstandard ketoconazole and
dissolvein(100ml)methanol, dilute( 1ml) of this solution to(10ml )with (50%) methanol.
Test:Take (1ml) of the sample, complete volume up to(10ml) methanol,
dilute 1ml of this solution to (10ml) with (50%) methanol.
Procedure: Separately inject equal volume about (20µl) of the standard and test solution into the chromatograph, record the chromatograms and measure the response for major peaks.
Calculation
Peak area of the test
% ketoconazole = --------------------------------------- X 100
Peak area of the STD.
Stability study:
Stability study was conducted on the product for( 6months)at different temperatures (room temperature,40,50,60 ) ◦C to determine the expiration date and the best storage conditions.
Results and discussion
Different formulas of suspension were prepared according to the specification of United state Pharmacopoeia(2010).A white homogenous suspensionof acceptable was produced and the physicochemical properties.
The product showed stability at different temperatures (25, 40, 50, and 60) ◦C.
Homogenous suspension of acceptable characteristics was obtained. Stability studies and physicochemical properties of the selected formula at different temperatures are presented in table (1). The calculations of expiry date from accelerated stability studies are presented in tables (2) and (3).
The product was chemically stable at all these temperatures.
According to this study the expiration date has been estimated to be not less than (2) years from the date of manufacturing at room temperature.
Table (1) -The physico – chemical changes of Ketoconazole Suspension (2%) with time at different temperatures .
Storage time (month) Temp. °C %of Ketoconazole
(90 -110)% PH
( 4-6.5) Appearance
Zero time R.T 100.2 6.1 White homogenous suspension
1 RT 100.9 5.96 White homogenous suspension
40 100.02 5.94 White homogenous suspension
50 98.66 5.84 White homogenous suspension
60 95.25 5.66 White homogenous suspension
2
RT 99.6 5.2 White homogenous suspension
40 97.0 5.7 Off White homogenous suspension
50 93.7 5.24 Faint Paige homogenous suspension
60 90.25 4.38 Paige homogenous suspension
3
RT 99.52 5.92 White homogenous suspension
40 96.32 5.84 Off White homogenous suspension
50 91.46 5.18 Faint Paige homogenous suspension
60 91.2 4.07 Paige homogenous suspension
4
RT 99.2 5.8 White homogenous suspension
40 93.05 5.66 Off White homogenous suspension
50 91.2 5.5 Pale Paige homogenous suspension
60 91.0 4.2 Brown homogenous suspension
5
RT 98.9 6.2 White homogenous suspension
40 92.5 5.9 Off White homogenous suspension
50 91.4 4.8 Pale Paige homogenous suspension
60 90.0 3.9 Brown homogenous suspension
6
RT 98.9 5.6 White homogenous suspension
40 92.1 5.4 Off White homogenous suspension
50 91.0 4.5 Pale Paige homogenous suspension
60 89.9 3.9 Brown homogenous suspension
Table (2)-The stability Study of ketoconazole Suspension, concentration of ketoconazole at zero time = 100.2 % of the label amount
Time at samples are to be assayed(days)
Temp. °C 30 day 60day 90day 120day 150day 180day Slope
R.T 100.9 99.6 99.52 99.2 98.9 98.9 -0.01126
40 100.02 97.0 96.32 93.05 92.5 92.1 -0.05369
50 98.66 93.7 91.46 91.2 91.4 91.0 -0.04301
60 95.25 90.25 91.2 91.0 90.0 89.9 -0.01685
Regarding the expiry date of the prepared formula we followed the Zero – order rate of reaction that is expected for kinetic of ketoconazole Suspension particularly in the first stage of reduction of concentration.T90%=0.1C/K
Where:
C=concentration at zero time
K= rate of reaction
T= time
Table (3)-The T90% at different temperature.
Temp °C Expire date /days Expire date/years
R.T 900 2.5
40 720 2
50 684 1.9
60 576 1.6
References
1- Sean C Sweetman, 2011, printed by LEGO S.P.A.,Martindale 37 the Complete Drug Reference, Pharmaceutical Press, USA.
2- Janet Woodcock, 2012, P.D.R 66 physicians’ desk reference,USA.
3- British Pharmacopoeia press, 2013, British Pharmacopoeia, U.K.
4 - United states Pharmacopoeia press, 2010, U.S.P 30, U.S.A.
5- Kim Huynh, (2009), Accelerating aging, Handbook of stability testing in pharmaceutical development, springer, USA. | en_US |
