The design of controlled release delivery system is subject to several variables of considerable important. Among these are the route of delivery of the drug, the type of delivery system, the disease being treated, the patient, the length of therapy and the properties of the drug. Each of these variables are interrelated and this imposes certain constrains upon choices for the route of delivery, the design of the delivery system and the length of therapy. The goal in controlled drug delivery system is to:

· Reduce the frequency of dose or to increase the effectiveness of the drug at the site of action, reducing the dose, or to form a uniform drug delivery.

· It could be a single dose for the treatment whether it is for days or weeks, as with infection, or for the life time of the patient, as in hypertension or diabetes.

· The safety margin of the drug which has the high potency that can be increased and thus the incidence of both local and systemic adverse effects can be reduced in the sensitive patient.

Orlistat is a lipase inhibitor for obesity management that acts by inhibiting absorption of dietary fats. It has short half life (< 2hrs) and requires administration three times a day. Hence it is considered as formulation of CR and IR formulations. The half life of Orlistat is 1-2 hrs, as it has been released immediately¹. By using controlled release dosage form the therapeutically effective concentration can be maintained for longer time than the conventional dosage form. Bilayer tablets are preferred when the release profile of the drugs is different from one another and has to be released in an immediate and controlled manner, so that therapeutic concentration can be maintained^2,3. Moreover Orlistat release should be less in stomach and further release should be increased in the intestine and completed within eight hours. Hence an attempt was made to develop a bilayer tablet comprising of Orlistat controlled release and immediate release layers⁴.

MATERIALS AND METHODS:

Methods:

Calculation of dose for bilayered tablet^5,6

The immediate release part of bilayered tablet was calculated using the following equation

DIR = Cp × Vd/F

Where Cp is target serum level,

Vd is volume of distribution and

F is bioavailability factor.

The total dose of Orlistat to deliver a once daily-controlled released formulation was calculated by the following equation using available pharmacokinetic data:

DSR = DIR (1 + 0.693 × t/t_1/2)

where DSR is a total dose of drug for sustained released layer,

DIR is dose of the immediate release part; t is the time (hours) duration for which the sustained release of the drug is desired and t_1/2is half-life of the drug.

Formulation of the immediate release layer:

The IR layer was prepared by passing the accurately weighed drug, sodium starch glycolate and 5% PVP as a dry binder through # 40 (420μm ASTM) as per the formulae given in Table 1. The sieved blend was transferred to a poly bag and mixed for 5 minutes. The obtained blend was lubricated for 2 minutes with magnesium stearate and amaranth passed thorough # 60 (250μm ASTM) and # 100 (150μm ASTM) respectively. Amaranth was added to differentiate the IR layer from the CR layer as shown in Table1.

Table 1: Formula of immediate release layer of Orlistat

Ingredients	Quantity (mg)
Orlistat	8
Sodium starch glycolate	8
Sodium saccharin	81
Magnesium stearate	1.5
Talc	1.5
Amaranth	1

Formulation of the controlled release layer:

The CR layer was prepared by blending the drug and the controlled release polymer (sodium alginate, ethyl cellulose, HPMC K 55M) individually, uniformly along with diluent and PVP K30 as a dry binder in a ploy bag as per the formulae given in Table 2 after sifting them through #40 (420μm). The resulting blend was lubricated with talc and magnesium stearate passed through # 60 (250μm).

Precompression studies of the prepared blend to be compressed into tablet:

Prior to the compression of the formulation blends into tablets, flow properties of the powders should be determined to check its suitability for compression. Angle of repose (AR), compressibility Index (CI) and Hausner’s ratio (HR) were used to characterize flow properties of the blends. The flowability of a powder is of critical importance in the production of pharmaceutical dosage forms in order to reduce dose variations^7-9.

Table 2: Formula of controlled release layer of Orlistat

Ingredients	F1	F2	F3	F4	F5	F6	F7
Orlistat(mg)	32	32	32	32	32	32	32
Sodium alginate (mg)	20	-	20	-	40	-	40
HPMC K55M(mg)	-	20	20	-	-	40	40
Ethyl cellulose(mg)	20	20	-	40	-	-	40
Microcrystalline cellulose(mg)	124	124	124	124	124	124	64
Magnesium stearate(mg)	2	2	2	2	2	2	2
Talc (mg)	2	2	2	2	2	2	2

Bulk density:

Bulk density of a powder is the ratio of the mass of the powder to the volume occupied by the loose powder bed. The unit volume includes the spaces between the particles and the envelope volumes of the particles themselves.

An amount of powder equivalent to 15g was accurately weighed and placed in a 50mL volumetric cylinder without compaction and the volume occupied was measured and the initial bulk density was calculated by the following equation. Each experiment was performed in triplicate and calculated using Equation 1.

ρ_bulk = M/V_bulk Eq. 1

where, ῥ_bulk = bulk density, M = mass of the powder and V _bulk = Initial volume of powder

Tapped density:

Tapped density of a powder is the ratio of the mass of the powder to the volume occupied by the powder after a fixed number of taps (100). The tapped density of a powder represents its random dense packing.

An amount of each powder of 15g was accurately weighed and placed in a 50mL volumetric cylinder. Then the cylinder was tapped by raising it to a height of 12–14mm and then allowing it to fall under its own weight. The final volume was recorded and the final tapped density was calculated by the following Equation 2. Each experiment was performed in triplicate.

ρ_tap= M/V_tap Eq. 2

where, ρ_tap= tapped density, M = mass of the powder and V_tap = Volume of powder on tapping

The bulk and tapped densities were used to calculate the CI and the HR.

Carr’s compressibility index:

Carr’s compressibility index (CI) of the powder was found by using the following Equation 3

X 100 Eq. 3

CI value can reflect the ease of powder consolidation. A higher CI values indicates its poor flow.

Hausner’s ratio:

The powder’s Hausner’s ratio (HR) is expressed as HR value reflects inter particulate friction. A high HR value means poor flow calculated using Equation 4.

HR= Eq. 4

Angle of repose:

Angle of repose (AR) has been used as an indirect method of quantifying powder flowability. AR for the blend of each formulation was determined by the fixed funnel method.^10,11

A glass funnel was secured with its tip positioned at a fixed height (h) above a graph paper placed on a horizontal surface. The powders were carefully poured through the funnel until the apex of the conical pile so formed just touched the tip of the funnel. The mean radius (r) of the base of the powder cone was determined and the AR (θ) was calculated as follows:

tan θ = h/r Eq. 5

where, h = height of the conical pile and r = radius of the conical pile.

The procedure was done in triplicate and the average AR was calculated for each powder. AR is a characteristic property related to inter particulate friction or resistance to movement between particles.

Compression of the bilayer tablet:

Initially the die was filled with CR blend and precompressed using 16 station, single rotary tablet compression machine (Cadmach Machinery Co. Pvt. Ltd., India) equipped with 6 mm round concave punches. Upon this precompressed CR layer, weighed quantity of IR blend was transferred manually followed by compression obtaining a bilayered tablet having hardness in the range of 6-8 kgcm^-2.

Evaluation of bilayered tablets:

The prepared bilayered tablets were subjected to quality control tests such as uniformity of weight, friability test, hardness, drug content and in vitro dissolution studies.

Uniformity of weight:

According to Indian Pharmacopoeia (I.P.)¹², 20 tablets were selected at random, weighed together and then individually. The mean and the standard deviation were determined.

Prepared tablets complies the test if not more than two of the individual weights deviate from the average weight (>250mg) by more than the percentage (5%) and none deviate more than twice that percentage.

Friability:

The friability test ¹³was carried out in dual chamber friabilator (Electrolab, India). Tablets equivalent to 6.5g were weighed (W0) initially and put in a rotating drum. Then, they were subjected to 100 falls of 6 inches height (25rpm for four min). After completion of rotations, the tablets were dedusted by using camel hair brush and weighed (W).

Hardness:

Tablets should be sufficiently hard to resist breaking during normal handling and yet soft enough to disintegrate properly after swallowing¹⁴. Five tablets were randomly selected and the hardness of each tablet was measured using Monsanto hardness tester. The mean hardness was determined and expressed in kg cm^-2.

Determination of drug content:

From each batch of prepared tablets, 10 tablets were randomly collected and powdered^15,16. Powder equivalent to 15.46mg of Orlistat was weighed accurately from each batch and were transferred separately to a 100mL volumetric flask. Volume was made up to 100 mL with pH 7.4 phosphate buffer and subjected for vortex mixing and sonication for dissolving the drug. Appropriate dilutions were made with pH 7.4 phosphate buffer and the amount of Orlistat was analyzed using a validated method at 378nm using a double beam UV/visible spectrophotometer (ElicoInd Ltd, India)^17-20. The drug content was calculated using Equation 6.

X 100 Eq. 6

In vitro dissolution study:

The in vitro release tests were performed using LABINDIA, Disso 2000, according to the US Pharmacopoeia 27; the compressed bilayered tablets were introduced into dissolution medium. A 900mL of phosphate buffer pH 7.4 was used as dissolution medium, rotational speed of the paddle was set at 50rpm at 37±0.5ºC. Aliquots (5mL each) were withdrawn at predetermined time intervals by means of a syringe fitted with a 0.45μm pre-filter and immediately replaced with 5mL of fresh medium maintained at 37±0.5°C. The samples were analyzed for Orlistat at 378nm using a double beam UV/visible spectrophotometer (ElicoInd Ltd, India). All the dissolution experiments were carried out in triplicate.^21-24

Release kinetics:

The analysis of drug release mechanism from a pharmaceutical dosage form is an important but complicated process and is practically evident in the case of matrix systems. As a model-dependent approach, the dissolution data was fitted to five popular release models such as zero-order, first-order, Higuchi, Hixon-Crowel and Korsmeyer Peppas equations. The order of drug release from matrix systems was described by using zero order kinetics or first orders kinetics and the mechanism of drug release by using Higuchi and Hixon-Crowel equation.

Zero order release kinetics is defined as a linear relationship between the fractions of drug released versus time²⁵. A plot of the fraction of drug released against time will be linear if the release obeys zero order release kinetics. It is given by Equation 7below:

Q = k₀t Eq. 7

where, Q is the fraction of drug released at time t and k0 is the zero order release rate constant.

In first order release kinetics, Wagner assumed that the exposed surface area of a tablet decreased exponentially with time during dissolution process, this suggests that drug release from most of the slow-release tablets could be described adequately by apparent first-order kinetics²⁶. First order kinetics is defined by Equation 8 below:

ln (1-Q) = −k₁t Eq. 8

where, Q is the fraction of drug released at time t and k1 is the first order release rate constant. Thus, a plot of the logarithm of the fraction of drug remained against time will be linear if the release obeys first order release kinetics.

Higuchi equation defines a linear dependence of the active fraction released per unit of surface (Q) on the square root of time. It is defined by Equation 9 below:

Q = k₂t½ Eq. 9

where, k₂ is the release rate constant. Hence, a plot of the fraction of drug released against square root of time will be linear if the release obeys Higuchi equation. This equation describes drug release as a diffusion process based on the Fick’s law, square root time dependent.

Erosion equation²⁷ defines the drug release based on tablet erosion alone (Equation 10).

Q = 1- (1-K₃t)³ Eq. 10

where, Q is the fraction of drug released at time t, K3 is the release rate constant. Thus, a plot between [1-(1-Q)^1/3] against time will be linear if the release obeys erosion equation.

In order find out the mechanism of drug release, first 60% drug release data were fitted in Korsmeyer Peppas model in Equation 11

M_t / M₈ = K₄tn Eq. 11

where M_t / M₈ is a fraction of drug released at time, t, K₄ is the release rate constant and n is the release exponent. The n value is used to characterize different release for cylindrical shaped matrices. For the case of cylindrical tablets, 0.45 = n corresponds to a Fickian diffusion mechanism, 0.45 < n < 0.89 to non-Fickian transport, n = 0.89 to Case II (relaxational) transport, and n > 0.89 to super case II transport.^27,28

Fourier Transform Infrared Spectroscopy:

Infrared spectroscopy was conducted using a Shimadzu FTIR 8300 Spectrophotometer and the spectrum was recorded in the region of 4000 to 400 cm^-1. The procedure consisted of dispersing a sample (drug and drug resinate mixture, 1:1 ratio) in KBr (200-400mg) and compressing into discs by applying a pressure of 5 tons for 5 min in a hydraulic press. The pellet was placed in the light path and the spectrum was obtained. Spectra were recorded in duplicate for each of sample.

RESULTS AND DISCUSSION:

Precompression studies of the prepared blend to be compressed into a tablet:

Powder flow properties are the important parameters which are crucial in processing operations such as mixing, flow of blend from hoppers to the turret for compression. One of the major problems encountered with these poor flowing powders in pharmaceutical industry is inconsistent and uniform flow from the hoppers. The angle of repose of the all blends (F1 to F7) was found to be ≤ 25° indicating excellent properties. The Carr’s index and Hausner’s ratio of the all blends was found to be ≤ 20% and 1.20-1.25 indicating good flow properties. Blend of all the batches used for compression of core tablets exhibited good flow and compression properties as the excipients used for the formulations were of directly compressible grade. The results in Table 3 had shown that the direct compression method can be used for the compression of tablets.

Evaluation of bilayered tablets:

The physical attributes of the tablet were found to be satisfactory. Typical tablet defects, such as capping, chipping, and picking, were not observed. Tablet properties like weight variation, thickness, hardness, friability and drug content of each batch was represented in Table 4.

Release kinetics:

To know the mechanism of drug release from these formulations, the data were treated according to first-order (log cumulative percentage of drug remaining versus time), Higuchi’s (cumulative percentage of drug released versus square root of time), and Korsmeyer’s (log cumulative percentage of drug released versus log time) equations, along with zero order (cumulative amount of drug released versus time) pattern. The release rate kinetic data (correlation coefficients) for all the equations can be seen in Table 6. When the data were plotted according to the zero-order equation, the formulations showed linearity with correlation coefficient values between 0.9177 – 0.9673 as shown in Figure 1. Release of the drug from a matrix tablet containing hydrophilic polymers generally involves factors of diffusion. Diffusion is related to transport of the drug from the dosage matrix into the dissolution fluid, depending on the concentration. As the concentration gradient varies, the drug is released, and the distance for diffusion increases. This could explain why the drug diffuses at a comparatively slower rate as the distance for diffusion increases, which is referred to as the square-root kinetics or Higuchi’s kinetics ³⁴. In this study, the in vitro release profiles of the drug from all the formulations could be best expressed by Higuchi’s equation, as the plots showed high linearity (r=0.9843 to 0.9403). To confirm the diffusion mechanism, the data were fit into Korsmeyer et al., equation. All the formulations showed good linearity (r = 0.9966 to 0.9002), with slope (n) values ranging from 0.3318 to 0.4195, indicating that diffusion was the dominant mechanism of drug release, with these formulations indicative of quasi-fickian diffusion.

Table 6: Kinetic values obtained from different plots of formulations F1 to F7

Formulation CR	Correlation coefficient (R²)
Formulation CR	Zero order plots	First order plots	Higuchi plots	Korsemeyer Peppa’s plots
F1	0.9346	0.8942	0.9403	0.9391
F2	0.9228	0.8331	0.9514	0.9002
F3	0.9619	0.9582	0.9843	0.9966
F4	0.9177	0.964	0.9636	0.9096
F5	0.9535	0.9574	0.9581	0.9024
F6	0.9673	0.9595	0.9458	0.9030
F7	0.9403	0.9589	0.9411	0.9770

Figure 1: in vitro release profiles of orlistat from bilayered tablet formulations (F1 to F7)

Fourier Transform Infrared Spectroscopy.

Optimized formulations F3 also exhibited the characteristic peaks of Orlistat with no additional peaks observed in the spectra, indicating retention of chemical identity of Orlistat. However, intensity of peaks corresponding to the drug was reduced or broadened in the optimized formulations possibly due to the mixing of other excipients.

CONCLUSION:

There is no controlled release tablet or bilayered tablet marketed dosage form of Orlistat, there is only immediate release tablet available. This is possible by formulating a biphasic release system which was achieved by bilayered tablet characterized by an initial rapid release by the IR layer followed by controlled release of drug from CR layer of bilayered tablet from the optimized formulation F3 which consists of sodium alginate and HPMC in 1:1 ratio of drug and polymer ratio. This result obtained was encouraging as HPMC has prolonged the release for 24 hrs which is natural in origin. Drug release is dependent on both the type and amount of polymer in the tablet. This biphasic release surmount the major disadvantages of controlled release matrix tablets by providing an additional initial burst release (i.e. loading dose form the IR layer) within 15 min followed by a constant release from controlled release layer over a defined period of time.

ACKNOWLEDGEMENT:

The authors are thankful to Dr. Lavu Rathaiah, Chairman, Vignan group of institutions, for providing necessary facilities to carry out research work.

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Received on 08.06.2020 Modified on 19.07.2020

Research J. Pharm. and Tech. 2021; 14(6):2976-2982.

DOI: 10.52711/0974-360X.2021.00521

Formulation	Angle of repose (AR)	Carr’s index (CI)	Hausner’s ratio (HR)
F1	24.8±0.02	13.1±0.02	1.14±0.02
F2	23.3±0.03	14.7±0.04	1.15±0.03
F3	24.6±0.02	10.5±0.05	1.10±0.02
F4	24.3±0.02	13.1±0.03	1.13±0.04
F5	23.3±0.03	10.8±0.02	1.10±0.03
F6	24.6±0.02	10.8±0.02	1.10±0.02
F7	24.3±0.03	16.6±0.03	1.13±0.02
O(IR)	24.1±0.02	12.9±0.04	1.24±0.03

Formulation	*Thickness (mm)**	Weight variation (mg) **	*Drug content (%)**	*Hardness (kg/cm²)**	*Friability (%)**
F1	3.96±0.55	298±0.24	84.31±1.12	3.76±0.76	0.79±0.02
F2	4.86±0.56	292± 0.20	86.28±1.11	3.76±0.78	0.82±0.03
F3	4.36±0.56	300±0.300	96.17±0.95	3.43±0.9	0.84±0.02
F4	3.93±0.54	298 ±0.24	81.15±0.91	3.86±0.97	0.75±0.04
F5	3.9±0.55	300 ±0.3	83.81±0.88	4.13±0.84	0.84±0.02
F6	4.46±0.56	302±0.34	88.06±0.66	3.16±0.56	0.87±0.02
F7	3.7±0.55	299± 0.26	89.31±0.84	3.6±0.44	0.83±0.03

		Cumulative % drug release
S. No	Time(h)	F1	F2	F3	F4	F5	F6	F7
1.	1	4.45	5.31	6.77	4.13	5.15	7.63	3.96
2.	2	15.31	20.91	23.32	20.34	24.43	24.53	12.68
3.	3	33.98	41.21	40.78	39.11	29.87	31.24	22.82
4.	4	52.09	59.46	51.67	54.53	34.56	44.94	36.09
5.	5	62.09	66.65	66.51	59.26	50.96	69.90	40.47
6.	6	79.79	78.99	78.28	61.13	58.39	79.69	52.27
7.	8	82.32	83.34	87.83	73.61	69.27	82.36	59.52
8.	10	82.66	85.41	92.70	76.89	79.84	99.97	63.01
9.	12	84.05	88.38	99.99	83.03	88.33	99.98	79.41