Development and Evaluation of Controlled Release Formulation of Zidovudine Based on Microporous Osmotic Tablet Technology Using Fructose as Osmogen

 

Chinmaya Keshari Sahoo¹, Surepalli Ram Mohan Rao², Muvvala Sudhakar³,

Kokkula Satyanarayana⁴

¹Ph.D Scholar, Pharmaceutics Department, Faculty of Pharmacy, University College of Technology, Osmania University,Hyderabad,Telangana-500007.

²Professor, Mekelle Institute of Technology, Mekelle University, Mekelle, Ethiopia.

³Professor and Principal, Department of pharmaceutics, Malla Reddy College of Pharmacy, Maisammaguda, Secunderabad, Telangana-500014.

⁴Professor and Principal, Department of pharmacognosy, Princeton College of Pharmacy, Korremula, Ghatkesar, R.R. District, Telangana India-500088.

 

ABSTRACT:

The present work was aimed to develop and evaluate controlled porosity osmotic pump (CPOP) tablets of an anti HIV drug zidovudine to provide a uniform concentration of drug at absorption site. The formulations were prepared by wet granulation method using drug, various excipients, controlled release polymer hydroxylpropylmethyl cellulose(HPMCE5M LV) and osmogen (Fructose).The CPOP tablets consist of an osmotic core coated with a micro porous membrane made up of cellulose acetate(CA) which is incorporated with sorbitol as porogen. Prior to compression the prepared granules were evaluated for pre compression parameters such as angle of repose, bulk density, tapped density, Carr’s index and Hausner’s ratio. After compression the prepared granules were evaluated for thickness, coat thickness, hardness, weight variation, friability, drug content, diameter, in vitro drug release study and scanning electron microscopy (SEM) study. The release kinetics for different formulations were analyzed using zero order model equation, first order model equation, Higuchi model equation, Korsmeyer Peppas model equation and Hixson-Crowell equation. The optimized formulation of drug release was independent of pH, agitation intensity, but dependent on the osmotic pressure of the release media. Based on the in vitro dissolution profile optimized formulation ZF4 exhibited Fickian transport mechanism with a drug release of 97.83% in 16 hrs. FTIR and DSC study revealed that there was no interaction between drug and excipients. Formulations subjected to stability testing (at 40±2ºC/75±5% RH) as per ICH guidelines for three months indicated stability with no significant changes in thickness, hardness, weight variation, friability drug content and dissolution profiles.

 

 

 

 

 

INTRODUCTION:

The drug release from conventional oral drug delivery system¹ is uncertain and unable to maintain effective concentration at the target site for longer period of time. Presence of food, pH of gastro intestinal tract, degradation by enzymes of GI fluid and change in GI motility affect the bioavailability of drugs in conventional drug system. To avoid these limitations controlled drug delivery system has taken major role in the pharmaceutical development to offer temporal or spatial control over release of drug. This can improve patient convenience and compliance, reduce in fluctuation in steady state plasma level so decrease intensity of local or systematic side effects and increase safety margin of high potency drugs. CDDS utilizes maximum amount of drug and reduces the total amount of dose administration of short biological half life drugs². Out of various CDDS osmotic drug delivery system (ODDS) is one of the most innovative drug delivery system which utilizes osmotic pressure as a driving force for controlled delivery of drugs. The of drug release  from osmotic³ system is not affected by  presence or absence of food, pH of gastrointestinal (GI) tract, GI motility and hydrodynamic conditions of body due to rate controlling semi permeable membrane. ODDS provide the drug release at predetermined zero order rate for prolonged period of time. Hence a uniform concentration of drug at the site of absorption is maintained in plasma concentration within therapeutic range which minimizes side effects and reduces the frequency of administration The current research is to develop controlled porosity osmotic pump tablets of zidovudine which comprises a core with the drug surrounded by semi permeable membrane of cellulose acetate and that is accomplished with different channeling agents of water soluble additives and pore forming agent in the coating membrane. When the controlled porosity osmotic pump tablets⁴ is in aqueous environment the water soluble additives get dissolved and forms micro porous structure in the coating membrane of regular and irregular shapes. The semi permeable membrane forms sponge like appearance in contact with water. The water enters through pores of semi permeable membranes and forms a solution of drug which releases through pores. Rate of water inlet is depending on type and concentration of osmogent and the drug release depends upon hydrostatic pressure created by inlet water, size and number of pores⁵. Over the past 36 years AIDS is spreading like a pandemic disease and creating major global health problem in world. WHO estimate in 2015 showed that 36.7 million people globally were living with HIV, AIDS killed 1.1 million people died from AIDS related illnesses and 35 million people have died from AIDS related illness since start from epidemic⁶. AIDS is a disease of human immune system caused by infection with human immune deficiency virus (HIV) where CD4 count declines 200cells/µL in blood⁷. AIDS was first recognized in the United States in June 5, 1981.The most common initial conditions of AIDS are pneumocystis pneumonia (40%), cachexia in the form of HIV wasting syndrome (20%) and esophageal candidiasis. Other common signs include recurring respiratory tract infections. Opportunistic infections may be caused by bacteria, viruses, fungi and parasites. These infections affect nearly every organ systeme. g. brain, eye, liver, genitals, skin etc. Patients with AIDS have an increased risk of developing various viral induced cancers including Kaposi’s sarcoma, Burkitt’s lymphoma, primary central nervous system lymphoma and cervical cancer.HIV is transmitted by sexual contact, contaminated blood transfusions, exposure to infected body fluids  or tissues and from mother to child during pregnancy, delivery or breastfeeding(vertical transmission).The management of AIDS can be controlled by antiretroviral therapy, male circumcision, needle exchange program, use of diaphragms, topical protection, use of condoms and alternative medicine. Zidovudine is FDA approved for treating adults and children with HIV infection as monotherapy or in combination with other antiretroviral agents. Zidovudine (3’-azido-3’-deoxythymidine) is a synthetic thymidine analog active against HIV-1,HIV-2 and human T cell lymphotropic virus(HTLV) I and II of class nucleoside reverse transcriptase inhibitor (NRTI).When zidovudine enters to host cell, it is phosphorylated by thymidine kinase to monophosphate then by thymidylate kinase to diphosphate and finally by nucleoside diphosphate kinase to active zidovudine-5-triphosphate.Zidovudine -5-triphosphate terminates viral DNA chain elongation by competing with thymidine triphosphate for incorporation into DNA⁸. Zidovudine has low therapeutic index, oral bioavailability of 60-70%, volume of distribution 1.6 lit/kg,plasma protein binding of 20-38%.,metabolism of 60-80% and renal excretion of 15%.The intracellular half life of zidovudine triphosphate  is about 3-4 hr⁹.Hence the present study CPOP tablets of zidovudine were formulated using wet granulation technique in order to reduce dose frequency of 600mg once daily for adults comparing to conventional dose and to enhance patient compliance towards therapy.

 

MATERIALS AND METHODS:

Materials:

Zidovudine was obtained from Hetero Drugs Pvt. Ltd. India. Fructose and mannitol were obtained from Qualigens Fine Chemicals, India. Cellulose acetate (CA) was obtained from Eastman Chemical Inc, Kingsport, TN.Sorbitol, HPMC E5M LV and polyethylene glycol (PEG) 400,600,4000,6000 were purchased from S.D. Fine Chemicals Ltd, Mumbai, India. Microcrystaline cellulose (MCC),magnesium stearate all are purchased from CDH, India. All other solvents and reagents used were of analytical grade.

 

Solubility Studies:

Solubility¹⁰ of drug in three different solvents (0.1N HCl pH 1.2 media, phosphate buffer pH 6.8, and phosphate buffer pH 7.4) was carried by preparing saturated solutions of drug in respective solvents. Saturated solutions were prepared by adding excess of drug to vehicles and shaking them on shaker for 24 hrs under constant vibration. After this, the solutions were filtered and analyzed spectrophotometrically.

 

Compatibility Studies:

Fourier Transform Infrared Spectroscopy (FTIR):

For pure drug, formulation and individual excipient were carried out by KBr pellet method¹¹ by using FTIR. The sample mixture and potassium bromide in the ratio of 1:100 was finely grounded using mortar and pestle. The small portion of mixture was placed under hydraulic press compressed at10kg/cm to form a transparent pellet which was kept in the sample holder and scanned from 4000cm to 400cm ^-1in FTIR spectrophotometer (BRUKER αE, Germany, OPUS).

 

Differential Scanning Calorimetry (DSC):

Physical mixtures¹² of drug and individual excipients in the ratio of 1:1 were taken and examined in DSC (Shimadzu DSC-50, Japan) by effective heat conduction and scanned in the temperature range of 50-300⁰C.The rate of heating was 20⁰C/min used to get thermogram. Then the themo grams were compared with pure samples versus optimized formulation.

 

Calculation of dose in sustained release tablets containing single drug:

For a sustained release matrix tablet formulation containing single drug can be calculated by following equations. The equations that were given by Robison and Erikson¹³ are based on the available pharmacokinetic data following one compartment model with simultaneous release of loading dose and maintenance dose with a zero order release kinetic. The equations are presented as follows:

 

D_L=Loading dose, D_M = maintenance dose, D_I=Initial dose; T = time for sustained action; T_max = Time to reach peak plasma concentration;

 

Elimination half-life (t_1/2) of Zidovudine is 0.5 to 3 hour (average 1.75); time to reach peak plasma concentration (T_max) = 0.8 hour; initial dose (D_I) = 300 mg.

Elimination rate constant

          0.693

K_E=-------------    (5)  = 0.693/1.75h= 0.396 h^-1

                t_1/2

                                 

Zero-order release constant K₀          = D_I × K_E

                                                                = 300 mg × 0.396 h^-1

                                                                = 118.8 mg/h

 

Loading dose D_L                                  = D_I − (K₀ × T_max)

                                                                = 300–(118.8 × 0.8h)

                                                                = 300 – 95.04

                                                                = 204.96 mg

 

So, maintenance dose         = Total dose – loading dose

                                                = 600 mg – 204.96 mg

                                                = 395.04 mg.

 

Hence, the CPOP tablet should contain a total dose of 600 mg for 16 hours in dosage form and it should release 300 − 95.04 = 204.96 (34.16%) mg in the 1st hour like conventional dosage form and the remaining dose (600 − 204.96) in remaining 15 hour, i.e. 395.04 (65.84%) mg or 26.336 (4.389%) mg per hour up to 16 hours.

 

Table 1: Theoretical profile of Zidovudine

Time(Hours)	Amount of DR in mg	%DR
1	204.96	34.16
2	231.296	38.549
3	257.632	42.938
4	283.968	47.327
5	310.304	51.716
6	336.64	56.105
7	362.976	60.494
8	389.312	64.883
9	415.648	69.272
10	441.984	73.661
11	468.32	78.05
12	494.656	82.439
13	520.992	86.828
14	547.328	91.217
15	573.664	95.606
16	600	100

 

Methods:

Preliminary solubility of Zidovudine:

The solubility of zidovudine was studied in different solvents like 0.1N HCl, phosphate buffer pH 6.8 and phosphate buffer pH 7.4 at 37±0.5⁰C.An excess quantity of drug was taken in 100ml of specified solvent. The solutions were shaken in water bath shaker for 24 hour at 37±0.5⁰C.The solution was then passed through a Whatman filter paper(No.1) amount of the analyzed spectrophotometrically at specified λmax of different solvents respectively. The solubility of zidovudine in 0.1NHCl (pH 1.2), phosphate buffer pH 6.8 and phosphate buffer pH 7.4 were 27.36, 20.10 and 20.11mg/ml respectively.

 

Preparation of Osmotic Pump Tablets:

The selected method for tablets preparation was by wet granulation technique¹⁴. Required weighed quantities of ingredients mentioned in Table-1 were passed through sieve No. 30 and lubricant and glidant were passed through sieve No. 80. All the ingredients were manually blended homogenously in a mortar by way of geometric dilution without adding lubricant (magnesium stearate), glidant (talc) to it. The mixture was moistened with aqueous solution and granulated through sieve No.30 and dried in a hot air oven at 60ºC for sufficient time (3-4 hrs). The dried granules were passed through sieve No.30 and blended with talc and magnesium stearate. The homogenous blend was then compressed into round tablets  with standard concave punches (diameter 10 mm) using 8 station rotary compression machine (Mini press, Karnavati, India).

 

Table 2: Composition of controlled porosity osmotic pump zidovudine tablets

Ingredients (mg)	ZF1	ZF2	ZF3	ZF4
ZD	600	600	600	600
MCC	175	150	125	100
Starch	40	40	40	40
HPMC E5LV	100	100	100	100
Fructose	25	50	75	100
Magnesium stearate	5	5	5	5
Talc	5	5	5	5
Total weight(mg)	950	950	950	950

 

Coating of Core Tablets:

The components of coating solution were mentioned in table 2. The coating solution was prepared using mixtures of CA 6gm and 33% w/w of cellulose acetate (CA) of polyethylene glycol 400, 600, 4000, and 6000 respectively with addition of acetone to quantity sufficient maintaining proper viscosity of solution. The coatings of tablets were performed by spray pan¹⁵ coating in a perforated pan (GAC-205, Gansons Ltd, Mumbai, India). Initially tablets were pre heated by passing hot air through the tablet bed and by rotating at a lower speed of 5-8 rpm. Coating process was started with rotation speed of 10-12 rpm. The spray rate and atomizing air pressure were 4-6 ml/min and 1.75 kg/cm² respectively. Inlet and outlet air temperature were 50ºC and 40ºC respectively. Coated tablets were dried at 50ºC for 12 hrs.

 

Table 3: Coating composition for zidovudine osmotic pump tablets

Ingredients	ZF1	ZF2	ZF3	ZF4
CA(g)	6	6	6	6
PEG 400(g)	2	0	0	0
PEG 600(g)	0	2	0	0
PEG 4000(g)	0	0	2	0
PEG 6000(g)	0	0	0	2
Sorbitol(g)	0	0.6	1.2	1.8
Acetone(mL)	300	300	300	300

 

Evaluation of Controlled Porosity Osmotic Pump Tablets:

Pre compression parameters of osmotic pump granules¹⁶:

Angle of repose (θ):

Angle of repose may be determined by heap shape measurement. The granules were allowed to flow through funnel freely onto the clean surface. Funnel was placed in such a height that bottom tip of funnel should not touched apex of heap of granules. Angle of repose is calculated using the following equation

tan=h/r                                                                                (6)

=tan^-1(h/r)                                                                            (7)

 

Where ϴ is the angle of repose, h is the height of heap in cm and r is the radius of the circular support (cone) in cm. It is shown in table no 4.

 

Bulk density (е_b):

Bulk density is determined by pouring the granules into a graduated cylinder of bulk density apparatus (Sisco, India). The bulk volume (V_b) and mass (m) of the granules is determined. The bulk density is calculated by using the following formula.

е_bm/V_b                                                                                 (8)

 

Tapped density (е_t):

The measuring cylinder containing known mass of granules blend is tapped 1000 times for a fixed time in bulk density apparatus (Sisco, India). The minimum volume occupied in the cylinder (V_t) and mass of the granules (m) is measured. The tapped density is measured by using the following formula.

е_t m/V_t                                                                                (9)

 

Compressibility index (Carr’s index):

The percentage compressibility of granules is a direct measure of the potential powder arch and stability. The Carr’s index can be calculated by the following formula.

%Carr’s index= e_t - e_b / e_t ×100                                        (10)

 

Where e_t is the tapped density of granules and e_b is bulk density of granules. It is represented in table no.4.

 

Hausner’s ratio (H_R):

Hausner’s ratio is used for the determination of flow properties of granules. The ratio can be calculated by the taking the ratio of tapped density to the ratio of bulk density. It is shown in table no.4.

H_R= e_t /e_b                                                                           (11)

 

Table 4: Scale of flow ability determined by different methods¹⁷

Flow property	Angle of repose	Compressibility index	Hausner’s ratio
Excellent	25-30	<10	1.00-1.11
Good	31-35	11-15	1.12-1.18
Fair	36-40	16-20	1.19-1.25
Passable	41-45	21-25	1.26-1.34
Poor	46-55	26-31	1.35-1.45
Very poor	56-65	32-37	1.46-1.59
Very very poor	>66	>38	>1.6

 

Post compression parameters of controlled porosity osmotic pump tablets [18]:

Thickness:

The thickness of individual tablets is measured by using vernier caliper (Absolute digimatic, Mitutoyo Corp. Japan).The limit of the thickness deviation of each tablet is ±5%.

 

Measurement of coat thickness:

After dissolution the film was isolated from the tablets and dried at 40⁰C for 1hr.Thickness was measured by using electronic digital calipers (Absolute digimatic, Mitutoyo Corp. Japan).

 

Hardness:

The hardness of tablets can be determined by using Monsanto hardness tester (Sisco, India) and measured in terms of kg/cm².

 

Friability:

Friability¹⁹of tablets was performed in a Roche friabilator (Sisco, India).Twenty tablets of known weight (W₁) were de-dusted in plastic chamber of friabilator for a fixed time of 25 rpm for 4 minutes and weighed again of weight (W₂).The percentage of friability was calculated using the following equation.

                              W₁-W₂

%Friability (F)   --------    100                                   (12)

                                 W₁

 

Where, W₁ and W₂ are the weight of the tablets before and after the test respectively.

 

Weight variation test:

Twenty tablets were randomly selected from each batch and weighed individually. The average weight and standard deviations of 20 tablets was calculated and compared with USP specifications. According to USP monograph the weight variation tolerance limit for uncoated tablets having average weight 13omg or less is by ± 10% where as for average between 130-324mg is by ± 7.5% and for average weight more than 324mg by ± 5%. The tablets meet the USP test if not more than 2 tablets are outside the percentage limit and if no tablet differs by more than 2 times the percentage limit.

 

Uniformity of Drug Content Test:

Ten tablets from each batch of CPOP formulations were taken and triturated to form powder. The powder weight equivalent to one tablet was dissolved in a 100ml volumetric flask filled with 0.1N HCl using magnetic stirrer for 24hr.Solution was filtered through Whatman filter paper No.1 diluted suitably and analyzed spectro photo metrically

 

 

Diameter of tablet:

The diameter of individual tablets²⁰ is measured by using vernier caliper (Absolute digimatic, Mitutoyo Corp. Japan) which gives the accurate measurement of diameter in mm. It provides information of variation of diameter between osmotic pump tablets.

 

In vitro Dissolution Studies:

In vitro dissolution test was carried out by using USP type II (paddle) apparatus. The tablet is kept in 900ml of dissolution fluid of 0.1N HCl (pH1.2) and stirrer rotating with 75 rpm and maintaining the temperature 37±0.5⁰C of dissolution media for first 2 hours then dissolution fluid is changed to phosphate buffer pH 6.8 maintaining same condition for next 14hrs. In specified time intervals an aliquot of 5ml samples of the solution were withdrawn through 0.45-μm cellulose acetate filter from the dissolution apparatus and with replacement of fresh fluid to dissolution medium. Absorbance of these solutions was measured at specific λmax using a UV/Visible Spectrophotometer (Shimadzu UV-1800, Japan). The drug release was plotted against time to determine the release profile of various batches.

 

Statistical data analysis:

The difference factor (f₁) calculates the percent error between the drug release profiles²¹ of two formulations usually one is test and other is standard over predetermined time points. It is expressed as

                                           (13)

 

Where n is the sampling number, Rj and Tj are the percent dissolved of the reference and test products at each time point j. Dissolution profile of test formulations are usually said to be satisfactory if f₁ values lie below 15.

 

The similarity factor (f₂) is a logarithmic transformation of the sum squared error of differences between the test Tj and reference products Rj over all time points.

f₂ = 50log [1+]^-0.5100         (14)

 

Where wj is an optional weight factor. The similarity factor fits the result between 0 and 100. Generally if f₂˃50, the release profiles are deliberated to be similar. For the calculation of similarity and difference factors of all the mentioned formulations in present studies three time points were taken i.e. I^st, 2^nd and 3^rd hours and dissolution profiles of theoretical release (reference) and test formulations at same time point were used.

 

 

 

 

In vitro drug release kinetic studies:

To analyze in vitro drug release kinetics^22,23 from the porous osmotic pump tablet, the in vitro release data were fitted by following equations.

 

Zero order kinetics for drug release can be expressed by the equation

Q_t = Q₀K₀t                                                                      (15)

 

Where

Q_t is the amount of drug dissolved in time t, Q₀ is the initial amount of drug in the solution and K₀ is the zero order release constant. The release kinetics can be studied by plotting cumulative amount of drug release versus time.

 

First order kinetics for drug release can be expressed by the equation: 

Log C = log C₀K₁t/2.303                                               (16)

 

Where C₀ is the initial concentration of drug, C is the amount of drug remaining to be released in time t, K₁ is the first order release constant. The release kinetics can be studied by plotting log cumulative percentage of drug remaining versus time. The first order release constant K₁ can be obtained by multiplying 2.303 with slope.

Higuchi model for drug release from matrix devices can be expressed by the equation.

Q = K_H √ t                                                                         (17)

 

Where Q is the amount of drug release in time t, K_H is the Higuchi dissolution constant. The release kinetics can be studied by plotting cumulative percentage of drug release versus square root of time. The slope is equivalent to K_H.

 

Korsmeyer-Peppas model (KP Model) for mechanism of drug release can be expressed as

Log (M_t/M_∞) Log K n Log t                                   (18)

 

Where M_t is the amount of drug release at time t, M_∞ is the amount of drug release after infinite time, K is the release rate constant incorporating structural and geometric characteristics of the tablet and n is the release exponent indicative of mechanism of drug release. The release kinetics can be studied by plotting log cumulative percentage drug release versus log time. In case of tablets (which are of cylindrical shape) a value of n 0.45 indicates Fickian or Case I release; a value between 0.45n0.89 shows non-Fickian or anomalous release; n0.89 for case II release and n0.89 indicates super case II release. Hixson and Crowell model for mechanism of drug release can be expressed by the equation

 

 

W₀^1/3  W_t^1/3  κ t                                                           (19)

Where W₀ is the initial amount of drug in the pharmaceutical dosage form, W_t is remaining amount of drug in the pharmaceutical dosage form at time t and κ is proportionality constant incorporating the surface volume relation. The release kinetics can be studied by plotting cube root of drug percentage remaining in matrix versus time.

 

Effect of osmogen concentration:

To determine the effect of osmogen concentration²⁴ on drug release formulations were prepared with different concentration of osmotic agents and all other parameters of tablet kept constant. The drug release was compared with the different osmogen concentration of formulated batches by using USP-II dissolution apparatus.

 

Effect of pore former concentration:

Different concentrations of pore former were used in semi permeable membrane formation. To know drug release characteristics and surface morphology in SPM in vitro drug release data as well as number of formation of micropores were compared.

 

Effect of membrane thickness:

Tablets with varying coating thicknesses²⁵ were prepared to determine the effect of coating thickness on drug release. The drug release rate was measured using 0.1NHCl(pH 1.2)for 2 hrs and phosphate buffer pH 6.8for remaining 14 hrs as a dissolution medium and compared with coating thickness variation of various dosage forms.

 

Effect of osmotic pressure:

To increase the osmotic pressure²⁶ of the release media pre-equilibrated to 37⁰C±1°C temperature and osmotic ally effective solute mannitol was added to produce 30 atm, 60 atm and 90 atm respectively. The drug release rate was tested and compared for various dosage forms.

 

Effect of pH:

In order to measure the effect of pH of release medium in the drug release of optimized formulation, the in vitro release study was carried in dissolution media²⁷ having different pH media. Dissolution can be carried in 900 ml of 0.1 N HCl, pH 6.8 phosphate buffer and pH 7.4 phosphate buffer in USP type II dissolution apparatus in 75rpm. The temperature was maintained at 37±0.5°C. The release was studied at predetermined time intervals.

 

Effect of Agitation Intensity:

To study the effect of agitation intensity²⁸ on drug release, optimized formulation was subjected to dissolution at various rotation speeds. Dissolution was carried out in USP-II (Paddle) at 50, 100 and 150 rpm. The samples were withdrawn at predetermined intervals and analyzed by UV spectrometer and the drug release for various batches was compared.

 

Scanning Electron Microscopy (SEM):

In order to predict the mechanism of drug release and surface morphology from the developed optimized formulations surface coated tablets before and after dissolution studies was examined using scanning electron microscope. The specimens²⁹ were fixed on a brass stub using double sided tape and then gold coated in vacuum by a sputter coater. Scans were taken at an excitation voltage (KV) in SEM fitted with ion sputtering device.

 

Accelerated stability studies:

The optimized formulation was subjected to accelerated stability studies as per ICH (The International Conference of Harmonization) guidelines by packing in air tight bottles that can withstand stressed conditions. The packed tablets³⁰ in air tight container were placed in stability chambers(Thermo lab Scientific equipment Pvt. Ltd., Mumbai, India) maintained at 40 ± 2 ºC, 75 ± 5% RH for 3 months. Tablets were periodically removed and evaluated for physical characteristics, drug content, in‐vitro drug release etc.

 

RESULTS AND DISCUSSION:

FTIR studies:

The study of the FTIR spectra of zidovudine demonstrated that the characteristic absorption peaks for the carbonyl group at 1638.76 cm^-1, N=N⁺=N stretching (azido group) at 2114.50 cm^-1,C-O stretching at 1063.08 cm^-1 and amine group stretching at 3317.86 cm^-1. This further confirms the purity of zidovudine. The major peaks of HPMCE5LV was found at 3880.71, 3669.20, 3013.82,  2444.13, 2335.14, 2216.90, 2068.70, 1821.07,1701.16,1661.47, 1536.52, 1500.67,1320.55, 1424.62,1188.15,1147.64, 1071.87,913.10, 781.05 and 584.97 cm^-1.The major peaks of fructose were found at 3450.75, 3120.47, 3047.75, 2722.80, 2464.30, 2310.70, 2102.48, 1914.04, 1502.21, 1391.71, 1102.14, 787.25, 677.36, and 599.13 cm^-1.In the optimized formulation containing fructose of osmotic pump (ZF4) peak at 3676.92, 3659.40, 2317.04, 1462.90, and 789.11cm^-1 were due to presence of the polymer HPMCE5LV.In the formulation the peaks present due to fructose were 3447.99, 2496.89, 2281.18, 1910.83, 1515.20, 1381.53, 994.59 and 670.82 cm^-1.Peaks at 2090.06 and 1695.43 cm^-1 were due to presence of the drug zidovudine in the optimized formulation. So from the study it can be concluded that the major peaks of drug 2090.06 and 1695.43 cm^-1 remain intact and no interaction was found between the drug, polymer and osmogen. Hence drug-excipient mixture reveals that here is no incompatibility was observed between zidovudine.

 

DSC thermo gram showed an endothermic peak at 114.5⁰C which is corresponding melting point of drug. DSC thermo gram showed an endothermic peak at 115⁰C in ZF4 formulation. Hence physical mixture showed that there was compatibility with the drug.

 

Figure 1: FTIR spectroscopy study of pure Zidovudine

 

Figure 2: FTIR spectroscopy study of ZF4

 

DSC Thermograms:

DSC thermo gram showed an endothermic peak at 114.5⁰C which is corresponding melting point of drug.

 

Figure 3: DSC thermogram of Zidovudine

 

Figure 4: DSC thermogram of ZF4

Table 5: Pre compression parameters of ZD formulations

Formulation code	Angle of repose (degree)a± S.D	Bulk density gm/ml)a± S.D	Tapped density (gm/ml)a± S.D	Carr’s Index (%)a± S.D	Hausner’s Ratioa± S.D
ZF1	30.12±0.12	0.467±0.03	0.532±0.02	12.21±0.06	1.13±0.03
ZF2	29.83±0.14	0.486±0.02	0.531±0.06	8.47±0.05	1.09±0.04
ZF3	27.32±0.09	0.482±0.12	0.528±0.11	8.71±0.09	1.09±0.08
ZF4	25.14±0.08	0.484±0.14	0.526±0.12	7.98±0.13	1.08±0.12

N.B.- All values are expressed as mean ± S.D, ^a n = 3

 

Pre Compression Parameters:

The pre compression parameters of various batches containing fructose follow as the angle of repose of pre-compression blends of various batches was in the range of 25.14±0.08 to 30.12±0.12.The bulk density of pre-compression blends was found to be in the range of 0.467±0.03 to 0.486±0.02gm/ml, tapped density in the range of 0.526±0.12 to 0.532±0.02gm/ml, the Carr’s index values were in the range of 7.98±0.13 to 12.21±0.06, and Hausner’s Ratio values were ranges of 1.08±0.12 to 1.13±0.03. (Table-1)

 

Post Compression Parameters:

All the post compression parameters for various batches evaluated accordingly such as thickness, coat thickness, hardness, friability, weight variation, drug content and diameter of tablet etc. The thickness of formulated tablets was found to be in the range of 4.51±0.02 to  4.594±0.02 mm, coat thickness in the range of 102.1±2.4 to 400.2±2.5µm, the hardness values were in the range of 7.3±0.13 to 7.8±0.11 kg/cm²,the friability values were in range of 0.09±0.03 to 0.17±0.01, average weight of tablet was in the range of  949.46±1.05 to 951.11±1.04 mg, drug content of tablet was in the range of 98.71±1.5 to 99.68±1.09 and diameter of tablets values were ranges of 12.12±0.06 to 12.15±0.11mm.It is depicted in Table 6.

 

Table 6: Post compression parameters of formulation

Formulation code	Thickness (mm)a± S.D	Coat thickness (µm)a± S.D	Hardness (kg/cm2)a ±S.D	%Friability (%)b± S.D	Average weight of tablet(mg)b ± S.D	%Drug contenta ±S.D	Diameter (mm)a ±S.D
ZF1	4.594±0.02	400.2±2.5	7.3±0.13	0.17±0.01	951.11±1.04	98.71±1.5	12.12±0.06
ZF2	4.513±0.03	302.2±3.1	7.4±0.12	0.16±0.03	949.46±1.05	99.35±1.07	12.13±0.07
ZF3	4.582±0.01	204.3±3.2	7.6±0.11	0.14±0.11	950.92±1.06	99.03±1.08	12.14±0.09
ZF4	4.51±0.02	102.1±2.4	7.8±0.11	0.09±0.03	950.22±1.04	99.68±1.09	12.15±0.11

N.B.-All values are expressed as mean S.D, ^a n = 10, ^b n = 20

 

In vitro drug release study:

The in vitro drug release characteristics were studied in 900ml of 0.1N HCl (pH1.2) for a period of first 2hrs and 3 to 16hrs in phosphate buffer pH 6.8 using USP type II dissolution apparatus (Paddle type).The cumulative percentage drug release for ZF1, ZF2, ZF3, ZF4 were 89.86, 92.38, 95.01 and 97.83% respectively of zidovudine at the end of 16hrs.It is shown in figure 5.

 

Figure 5: In vitro release profiles showing Zidovudine release from various fabricated formulations ZF1-ZF4

 

Statistical analysis:

Table 7: Similarity (f₂) and difference (f₁) factor with dissolution profile of all formulations

 

Kinetic model:

Table 8: Fitting of IVDR data in various mathematical models

Models	Zero order		First order		Higuchi		Korsmeyer-Peppas			Hixson-Crowell
Batches	R2	K0	R12	K1	RH2	KH	n	RK2	Kkp	R2	Ks
ZF1	0.960	4.494	0.863	0.1059	0.942	20.28	0.487	0.925	19.054	0.921	0.120
ZF2	0.962	4.845	0.888	0.1335	0.961	22.05	0.480	0.935	21.527	0.942	0.142
ZF3	0.960	4.959	0.888	0.1497	0.967	22.66	0.459	0.921	23.550	0.950	0.154
ZF4	0.942	5.045	0.873	0.1819	0.990	23.55	0.45	0.969	26.302	0.96	0.173

 

Figure 6: In vitro release profiles showing Zidovudine release from various fabricated formulations ZF1-ZF4 having different concentration of osmogen

 

 

Effect of osmogen concentration:

The core formulations were prepared with various concentrations of osmogens. The drug release profile is shown in figure 6.It is observed that osmogent enhances the drug release of drug and thus had a direct effect on drug release. The concentrations of osmogen were 25, 50, 75 and 100mg/tablet for ZF1, ZF2, ZF3 and ZF4 respectively

 

Effect of pore Former Concentration:

To study the effect of pore forming agent core formulations of zidovudine were coated with varying coating compositions of pore forming agent containing 0%, 10%, 20% and 30% w/w of CA of sorbitol for ZF1,ZF2,ZF3 and ZF4 respectively..Release profile from these formulations is shown in figure 7.It is clearly evident that the level of sorbitol had a direct effect on drug release. As the level of pore former increases the membrane becomes more porous after coming contact with aqueous environment resulting in faster drug release.

 

Figure 7: In vitro release profiles showing Zidovudine release from various fabricated formulations ZF1-ZF4 having different pore formers

 

Effect of Membrane Thickness:

The osmotic pump coated tablets having varying the coating thickness are evaluated for drug release study. Release profile of zidovudine from these formulations is shown in figure 8.It is clearly evident that drug release decreases with increase in coating thickness of the semi permeable membrane.

 

Effect of osmotic pressure:

The results of release studies of optimized formulation in media of different osmotic pressure indicated that the drug release is highly dependent on the osmotic pressure of the release media. The release was inversely related to the osmotic pressure of release media (figure 9). This finding confirms that the mechanism of drug release is by osmotic pressure.

 

Figure 8: In vitro release profiles showing Zidovudine release from various fabricated formulations ZF1-ZF4 having different membrane thickness

 

Figure 9: In vitro release profiles showing Zidovudine release from best ZF4 in different osmotic pressures

 

Effect of pH:

It is observed that there is no significant difference in the release profile, demonstrating that the developed formulation shows pH independent release. It is shown in figure 10.

 

Figure 10: In vitro dissolution study of best formulation ZF4 in various pH media

 

Effect of agitation intensity:

It shows that the release of zidovudine from CPOP is independent of agitational intensity. Hence it can be expected that the release from the developed formulation will be independent of the hydrodynamic conditions of the absorption site. It is shown in figure 11.

 

Figure 11: In vitro dissolution study of best formulation ZF4 in various agitation speeds

 

Scanning Electron Microscopy (SEM):

The coating membrane of the osmotic delivery system before and after dissolution was examined with the help of SEM. Before dissolution no pores were found in the coating membrane. But after dissolution comparatively more numbers of pores were found in the membrane might be due to leaching or removal of entrapped drug from the formulation. The porosity nature of the membrane was due to the presence of pore forming agent sorbitol in the formulation.

 

a

 

b

Figure 12: a) ZF4 formulation before dissolution, b) ZF4 formulation after dissolution

 

Stability Studies:

The short term stability for optimized formulation ZF4 shows that there was a not significant change in physical appearance, friability, hardness, drug content and in vitro drug release.

 

CONCLUSION:

Porous osmotic pump based drug delivery system of tablets were developed for controlled delivery of zidovudine. It was observed from the results that rate of drug release can be controlled through osmotic pressure of the core, the level of pore former and membrane thickness. Hence the current technology for designing of tablets can produce more advantage than conventional tablets.

 

ACKNOWLEDGEMENTS:

The authors would like to acknowledge the contributions of Pharmaceutics Department, Faculty of Pharmacy, University College of Technology, Osmania University, Hyderabad, Telangana, India for providing necessary facilities to carry out the research work. This study was part of a Ph. D. thesis under Osmania University, Hyderabad.

 

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