CHAPTER-03 ORLISTAT ORODISPERSIBLE MINI-TABLETS ...shodhganga.inflibnet.ac.in/bitstream/10603/57561/12/12_chapter-3.pdf · ORLISTAT ORODISPERSIBLE MINI-TABLETS: FORMULATION AND EVALUATION

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CHAPTER-03

ORLISTAT ORODISPERSIBLE MINI-TABLETS: FORMULATION AND

EVALUATION

3.1 INTRODUCTION

Obesity is one of the fast growing epidemic disease that when occurs causes many

chronic co-morbid disorders. In the last two decades obesity and eating disorder or over

eating have became a big challenge for the physicians treating the obese patients, and has

become the source of anxiety for the obese patients worldwide (V. Hainer and Hainerov

2012, J.C Seidell 2014).

Obesity develops in a person when high calories food intake exceeds energy consumption

for a long period leading to obesity and obese individuals are always at increased risk for

cardiovascular diseases, and diabetes (Bray et al., 2004, Lewis Landsberg et al., 2013).

Pharmacotherapy or medication for the treatment of the obesity have played a significant

role in reducing the weight and are an integral part of management of obesity especially

its comorbid diseases. Medications for the obesity are generally classified into three sub

classes; first class of drugs are those that controls the apetite, second of drugs are those

that induces thermogenesis and third class of drugs are those drugs that alter the

biotransformation like, ORL (G. A. Bray 2005). Among the various class of drugs for the

obesity presently, ORL (reversible inhibitor of enzyme lipesas in the GIT) is the only

drug US-approved medicine for obesity for longer course. It is available commercially in

60mg and 120mg dose only as capsule dosage form (Colon-Gonzalez F et al., 2013).

Tablets are the maximum used varstile solid dosage form but they too have some

limitations like, difficulty in swallowing for some people and delay in the onset of action

by few minutes (Habib, W et al., 2000). Rapid-disintegrating tablets (RDTs) and

Orodispersible tablets (ODTs) are meant to disintegrate the tablet in less than a minute

into a suspension or solution form when comes in contact with the aqueous fluid. RDTs

and ODTs are especially more acceptable and appreciated by people who have difficulty

in swallowing. In the last decade RDTs and ODTs, have become one of the popular

dosage form because of ease of administration that provide rapid onset of action (Reddy

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L. H et al., 2002, Parkash V et al., 2011). In addition, RDTs and ODTs have been

established in providing the maximum efficacy especially of low aqueous soluble drug

through fast disintegration and dissolution rate with enhanced bioavailability (S.S.

Biradar et al., 2006). Mini- tablets are novel multiple unit solid dosage form which are in

the size equal to or smaller than three milli-meters in diameter. Mini-tablets have many

advantages incomparison to the granules and pellets in size and shape without multiple

coating is required. However, mini-tablets can be coated with film to enhance the

stability and require less coating material providing good mechanical stability (Munday,

D.L., 1994, Lennartz, and Mielck, 1998).

Unlike conventional tablets which must be administered or swallowed using some liquid,

Orodispersible (ODTs) formulations doesn’t require any liquids for administration. ODTs

can be taken anytime anywhere without any liquid. In addition provide rapid onset of

action, increase patient compliance i.e., convenient to sallow with an acceptable taste

even without water. Orodispersible rapid disintegrating dosage forms are therefore

getting popular both with the patients and the physicians (Zygmunt A, et al., 2002).

3.2.0 Objectives of the Study:

The part of research project was to develop stable Orodispersible mini-tablets of ORL

(ORMTs), for the treatment of obesity with enhanced onset of action, reduced difficulty

in swallowing and improve the patient compliance and enhance the effectiveness.

With these objectives the following plan of work was designed:

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3.2.1 Plan of work for the preparation of ORMTs:

• To perform preformulation studies of API and to choose suitable excipients based

on drug excipients compatibility studies.

• Enhancing the solubility and the stability of API(ORL) by applying a suitable

technique

• Formulation design and compression of the ORMTs using multiple tip 3mm

punches

• Physicochemical Evaluation of the prepared ORMTs as per the standard methods

• Perform the in-vitro drug release study as per the monograph.

• To evaluate the organoleptic properties of optimized ORMTs formulation

• Finally to conduct a short period stability study.

3.3 MATERIALS AND METHODOLOGY

3.3.1 MATERIALS

ORL was procured gift sample from RA Chem., Pvt Ltd. Hyderabad.

Pharmabrust-500 and Pearlitol flash of SPI Pharma and Roquette Pharma respectively

and D-Sorbitol of Qualichem were obtained from the SL drugs & pharmaceuticals

Hyderabad. Ludiflash, Ludipress and Kolliphor P188 were the generous gift sample from

BASF Pvt Ltd. Mumbai. Vanilla flavor, Sucralose and Colloidal silicon dioxide were

obtained from Aizant Pharma, Pvt Ltd. Hyderabad. Other excipients including the β-

cyclodextrin used in the project were purchased from SD fine chem. Pvt Ltd. Mumbai.

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3.3.2 Equipments Used in the Project work:

Equipments to be used in the present project work are listed in the below table.

Table-06 List of equipments

S.

No. Name of instruments Manufacturer Model

1 Bi-layer Tablet compression

machine

Karnavathi Rimek II DL 9

STATION

2 Dissolution Test Apparatus Electrolab TDT-08L

3 UV-Vis Spectrophotometer Shimadzu UV-1800

4 HPLC Perkin Elmer 200 Series

5 Disintegration Test apparatus Electrolab ED-2AL

6 Sonicator Prama Instruments SONI-111

7 Electronic Analytical balance Afcoset Pvt, Ltd ER-182-A

8 Millipore Distilled water System Millipore Pvt, Ltd MILLI Q

9 Tablet Friabilator Electro Labs EF-2(USP)

10 Tablet Hardness Tester Dr Schleuniger

Pharmatron

8M

11 Water bath Shaker Remi DS451

12 Melting Point Apparatus Analab THEMOCEL

10

13 Digital pH meter Elico Ltd ATC(CL51B)

14 Bulk density apparatus Electrolab ETD 1020

15 Dry Granulator- Kalweka Karnavati Rimek DGS-2

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3.4 EXPERIMENTAL METHODS:

3.4.1 Preformulation Study:

3.4.1.1 Physical Characterization of the API and the Excipients:

In the physical characterization of the active and nonactive pharmaceutical ingredient the

evaluation was done manually by examining the colour odour and taste utilizing human

senses.

3.4. 1.2 Identification of Pure drug or Active pharmaceutical ingredient:

Purity of the active pharmaceutical ingredient was characterized by determining the

melting point, Lambda max by UV spectroscopy, FTIR spectra.

3.4. 1.3 Determination of Melting Point (M.P)

Determination of melting point of an active pharmaceutical ingredient is carried out by

capillary method using instrument µ Thermocol 10 (Ana lab Scientific). By following the

standard procedure, first the sample API is carefully loaded into the capillary tube

through the open end by gently pressing the API into the capillary tube several times.

When the powder is pushed to the bottom of the capillary tube, then sample tube is kept

into one of the sample position slots located on top of the instrument. Then the maximum

heating cut off temperature is set to avoid overheating and the melting point apparatus is

started to run. Then the observation is done visually through the magnifying lense

attached to the apparatus. When the sample or API nears the reference melting point, it is

keenly observed to check the actual melting point temperature. When the sample melts,

that temperature is noted down as it is the actual melting point temperature of the sample.

3.4. 1.4 ORL λ Max Determination in Methanol by UV Spectroscopy:

In this UV spectroscopic analysis of ORL λ max first a VF of 200ml was taken and few

milliliter of methanol is added then accurately weighed 200 mg or ORL was added and

the VF volume was made upto the mark by adding methanol. This suspension is shaken

vigorously first utilizing the cyclo mixture and then the bath sonicator for one hour. Once

the clear stock solution is formed it is filtered and is considered as the standard stock

solution. This std. stock solution is further used for preparing the different concentration

of ORL utilizing methanol as the diluting solution. Finally the different concentrations of

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the ORL prepared are analyzed by UV spectroscopy between 190-390 nm, to find the λ

max of ORL.

3.4. 1.5 Comparison of the FTIR Spectra:

The FT-IR spectra of the pure drug ORL and drug in combination with other excipients

were recorded with ABB Bowen Series spectrophotometer over the region of 400 – 4000

cm-1 by adopting Potassium bromide disc method at Sipra Labs, Hyderabad. The

compatability of the active and nonactive substances was analyzed utilizing the FT

infrared spectroscopy. In this method the FTIR spectrum of the pure drug is compared

with the FTIR spectrum of pure drug containing the excipients by overlapping both the

spectras.

3.4. 1.6 FTIR Sample Measurement Method:

There are two common methods for the solid sample preparation in the FTIR

spectroscopy; KBr disc method and Nujol method. In the present project work KBr Disc

method was utilized and the procedure is explained below:

3.4. 1.7 KBr Disc Method: In this method as the name indicate a 13mm diameter

discs are prepared by taking 0.1 to 1% sample and are mixed with approximately 200 to

250 mg of KBr powder. Then this mixture is finely pulverized and passed through the

200µ sieve and dried at around 110 °C. Removal of air and is done by degassing

procedure and stored in a desiccator. The sample is then placed into a disc forming die

and approximately eight to ten tons of pressure is applied under a vacuum of several mm

Hg for several minutes to form a transparent disc. The API+ KBr powder formed disc is

now ready to record the FTIR spectra by placing in the instrument and running

approximately between the regions of 4000 to 200 cm-1. When performing the FTIR

measurements the background can be measured with the empty disc of KBr free from the

active ingredient, by inserting into the sample chamber. This is done prior to taking the

actual spectrum of the sample, so that to ensure that the infrared light absorption by the

KBr or moisture absorption is nullified.

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3.4. 1.8 Drug- Excipients Compatibility Studies:

DRUG No Interaction

1:1 Mixture FTIR Excipients Recommend

Excipients Alternative Excipients? Interaction

Fig. 17 Schematic representation of compatibility studies

The drug and excipients compatibility was determined by taking the drug and excipients

blends in the ratio of 1:1. The total weight of this blend was 200mg. In the drug-

excipients compatibility study several key factors are determined such as the change in

the physical appearances, pH, and moisture using the appropriate instruments and more

importantly the changes in the chemical structure was evaluated by using the IR

spectroscopy and HPLC (Abu Serajuddin T. M, et al., 1999).

3.4. 2 Analytical Methods Development:

3.4. 2.1 Preparation of Buffers and Reagents

a) Sodium hydroxide solution, 0.2 M:

Required quantities and different concentrations of sodium hydroxide solution was

prepared following the method in the standard monograph.

b) Hydrochloric acid solution, 0.2 N:

Required quantities and different concentrations of hydrochloric acid solution was

prepared following the method in the standard monograph.

c) Di hydrogen Potassium Phosphate, 0.2 M:

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Required quantity of this solution was also prepared by following the standard

monograph. The required weighed quantities of above solid as described is taken and

mixed well with the required quantity of distilled water.

d) Phosphate Buffer pH 3:

All the buffers required in the project work are prepared following the method

described in the pharmacopeias. By taking the required quantities of the solid

substances and dissolving properly in the distilled water.

3.4. 3 UV Estimation Method for ORL:

i. ORL Stock Solution (1000 µg/ml) in Methanol:

200 mg of ORL was accurately weighed, transferred into a 200 ml volumetric flask,

dissolve in methanol little approx. 20ml of methanol and make up the volume to 100ml

with methanol.

ii. Standard graph of ORL in Methanol:

From the methanol stock solution, prepare 20, 40, 60, 80,100, 120, 140, 160, 180, 200

µg/ml dilutions using methanol. Measure the absorbance of each sample at λ max taking

methanol as blank. Plot a standard carve of concentration varsus absarbance, to obtain the

regretion eqaution.

Stock Solution of ORL in 3% SLS aqueous Solution:

ORL (1000 µg/ml):

200 mg of ORL was accurately weighed, and transfer into a 200 ml V.F, dissolve in the

little quantity of methanol and make up the volume with 3 % SLS up to 200ml.

iii. Estimation of λ max of ORL Water + 3% SLS by UV Spectrophotometer:

From the standard stock solution, Transfer 10 ml of the above solution in to a 100 ml V.F

and make the volume up to 100 ml with the Water + 3 % SLS (100 µg/ml). Take the UV

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scan for this solution (100 µ g/ml) between 200-400 nm. Determine the λ max from UV

spectra of ORL.

iv. Standard graph of ORL in Water + 3% SLS:

From the above stock solution, Prepare 20, 40, 60, 80,100, 120, 140, 160, 180, 200 µg/ml

dilutions using Water + 3% SLS. Measure the absorbance of each sample was at λ max

against Water + 3% SLS as blank. Plot a standard carve of concentration varsus

absarbance, to obtain the regretion eqaution.

3.4. 4 HPLC Method Development for ORL:

3.4. 4.1 A Liquid Chromatography method development for the determination of

ORL in the formulation

A HPLC method utilizing the reverse phase was developed and validated as per the

guidelines of ICH for the estimation of ORL in the formulation. A HPLC System made

by Perkin Elmer 200 Series equipped with UV-detector using (RP-18e (5µm)

Lichrospher® 100 column). The wavelength for UV detection was set at 210 nm. The

mobile Phase composition was acetonitrile and the phosphoric acid buffer of pH3 in the

ratio of (95:5), at the mobile phase flowing rate of 1.2 ml/min the HPLC was run for

twelve minutes.

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Table-07 HPLC method development of ORL parameters

Apparatus used HPLC (Perkin Elmer Series 200)

Column Lichrospher® 100

RP-18e (5µm)

Mobile Phase ACN : Buffer- pH 3 (95:5)

Flow rate 1.2 ml/min

Absorbance 210 nm

Injection volume 50 µl

Run time 12 min

3.4. 4.2 HPLC Validation Parameters: (As per the ICH Guidelines).

Performance Characteristics: are defined as a set of quantitative, experimentally

determined values for parameters of basic necessity in assessing the suitability of the

method for the given analytical purpose. The HPLC validation requirement that should be

considered are

i. Precision

ii. Accuracy

iii. Selectivity

iv. Linearity

v. Detection limit (DOL)

vi. Quantification limit (QOL)

vii. Robustness

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3.4. 4.3 Development and Validation of Analytical Methods or Procedures:

i. Precision: The precision is the determination of how much exact is an analytical

method. It is therefore the extent of the coefficient of correlation between a series of

analytical measurements obtained from the no. of sampling of the same single sample

under the standard procedures. The precision of analytical results is expressed as the

variance, standard deviation, coefficient of variation in the series of analytical

measurements.

ii. Accuracy: Accuracy is an important characteristic of validation procedure it is

the measure of knowing correctness of the analytical method. Accuracy is generally

determined by adding known amounts of analyze to a blank and establishing the percent

which is recovered.

iii. Selectivity: or specificity is knowing how much specific the analytical procedure

developed. It is determined by measuring the analyte in the mixture of impurities called

as compounds impurities, degradents and known excipients.

iv. Linearity: is the extent of proportionality of an analytical method. Linearity is

used to elicit test results that are directly proportional to the concentration of analyte in

samples within a given range. Linearity is usually expressed by the correlation coefficient

of the linear regression analysis. The slope and intercept of the line are also useful

parameters relating to linearity.

v. Range: is the area of variation that is acceptable between the upper and lower

levels of analyzing limits, where the method has been validated. The range is determined

form 50% to 150% of the nominal concentration of the dosage form.

vi. Ruggedness: is as the validation parameter that measure the reproducibility of the

method under normal expected operational conditions. Ruggedness is generally evaluated

by determining precision with two analysts on different instruments on different days.

Ruggedness may also include stability of solutions and evaluation of different columns

from different vendors.

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3.4. 4.4 Validation of a Quantitative Analytical Method

System suitability is a set of empirically determined parameters that are set to assure that

the total method and chromatographic system are functional prior to acceptance of any

given set of analysis.

Procedure

1. The performance characteristics of the analytical method have been previously

established. The attached procedure defines the operating parameters including

the column, solvent system, flow rate and injection volume.

2. All data gathered as part of this protocol will be evaluated by peak height and

peak area. Duplicate injections will be employed to decrease chromatographic

variability. As indicated in the method, duplicate injections that differ by more

than 4.0% will be repeated.

3. The extraction procedure will be validated by varying the extraction time and

completing the sample preparation and analysis as indicated in the attached

method.

4. The precision of the method will be determined by the following steps:

a) Determine the precision of the drug substance method by analyzing ten

aliquots of drug substances.

b) Determine the precision of the drug product method by analyzing 10

sample preparation from a single lot

c) Determine the precision of the drug substance and drug product methods

as described above with a second analyst

d) Determine the precision of the chromatographic system by one analyst

doing ten replicate injections of a single standard preparation.

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e) Report the mean (as a percent of theoretical) and the relative standard

deviation for each analyst, for the method and for the chromatographic

system.

5. Determine the selectivity of the method by injecting model compounds,

impurities, degradents and know excipients in the presence of drug substance

standard:

Determine the resolution between the active and the closest eluting compound as

a measure of the selectivity of the method.

6. Because of the desire to use the method for the quantitation of tablets, dissolution

samples and cleaning validation samples the linearity will be validated over a

broad range and concentrations of standard and two assays per concentration.

a) The standard curve for tablets and dissolution samples will be from

approximately 20 µg/ml to 400 µg/ml.

b) The standard curve for validation of linearity for cleaning validation

samples will be from approximately 0.10 µg/ml to 10 µg/ml.

c) Linear regression of the data will include a correlation coefficient, slope

and intercept.

7. The range of the method by definition will be the range validated in the linearity

experiments.

8. The accuracy of the method is determined utilizing the linearity data. Express the

accuracy as percent, recovered at each concentration and as an overall accuracy

when the data are normalized to percent of theoretical.

9. Limit of Quantitation and the Limit of Detection are determined form then

linearity data at the lowest concentrations.

a) The Limit of Quantitation will be determined from the standard deviation of

the response and slope and will be:

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LQ=10SD/Slope

b) The Limit of Detection will also be determined from the standard deviation of

the response and slope and will be:

LD=3 SD/Slope

10. Determine the ruggedness of the method with two analysts on a different

instrument and each analyst preparing and analyzing ten samples on each of two

days.

a) The data are reported be day, by analyst and as an overall precision of the method.

b) Column vendor evaluation (as part of ruggedness) will be performed at the same

time by using different columns from different manufacturers.

11. The stability of the standard solution and a sample solution will be determined at

time periods representative for storage (0, 24, 48, 72 hours and 5 and 7 days) by

comparing all data to the initial peak area and height of the standard. Stability will

be determined at ambient light and temperature.

System suitability has been previously established and includes precision six replicates

(RSD≤2%) plus resolution (≥ 1.8).

1. Precision of the chromatographic system ≤ 1.0%, precision of the method ≤ 2.0%.

2. Resolution between the active peak and the closest eluting peak will be ≥ 1.8.

3. Linearity criteria are a correlation coefficient ≥0.99 with the intercept not

significantly different from zero at the 95% confidence level.

4. Accuracy ± 5% at all concentrations.

5. A stable standard and sample will be determined by six replicate injections and

will have mean peak values within 5% of the initial means peak value.

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3.4. 4.5 Responsibility:

1. The responsibility for validating the analytical method including write up of the

method and the method validation report resides with analytical development.

2. Quality Assurance is responsible for audit of the data and approval of the method

and method validation report.

3.4. 4.6 The ICH Requirements for the HPLC Validation Parameters:

a) Accuracy ICH Requirement:

As per the ICH guidelines the accuracy must be determined taking min. three

concentrations level for the at least nine determinations. In the simple terms three

different concentrations should be replicated thrice.

b) Precision ICH Requirement:

The ICH guidelines require that the precision should be carried out with the specified

range of procedure taking minimum number of SLS determinants. In the simple terms

three different concentrations should be replicated thrice at cent percent of the test

concentration taking min. of six estimations.

c) Linearity ICH Requirement:

For the confirmation of linearity as per the ICH guidelines the under the specified range

atleast five different concentration are used. For determining the purity of active

pharmaceutical ingredient or drug in the dosage form formulations, the concentration in

the range of 25% to 150% of the test should be used.

d) Limit of detection ICH Requirement:

There are two method used for the limit of detection. The first one is the determination

based on visual observation and the second is based on the results of the signal to noise

ratio. For this relevant chromatograms should be considered acceptable for the

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justification. In the process of limit of detection in analysis by HPLC method if it is

estimated by extrapolation and calculation then, it should be validated by analyzing the

required number of samples that are closer to the detection limit.

e) Limit of Quantification ICH Requirement:

The quantification limit or the limit of quantifying of the analytical method developed for

quantifying should be presented in detail. The limit should be further validated by

analyzing with the suitable number of samples that are near to the quantification limit

need to be prepared.

3.4. 5 Physico-Chemical Evaluations:

3.4. 5.1 Solubility study of the pure ORL:

Solubility study of the pure ORL and with ORL β-CD complex was carried out. The

solubility study of the ORL in distilled water was carried out following the gold standard

method called shake flask. Excess amount of the API (ORL) was taken in a 50ml conical

flask with a closure to this 20ml of water was added. And this suspension is shaken at

room temperature on a shaker bath (Remi) at 100 rpm for 48h. Then solution was first

centrifuged, and the supernatant layer was filtered using the branded filter paper of 0.45µ

and the filtrated solution was diluted suitably and the drug content in water was

determined by analyzing using HPLC.

3.4. 5.2 Partition Coefficient Study:

Partition coefficient study was performed by saturation shake flask method by using the

octanol-water system; in this method both the liquid are taken in the separating funnel

bottle and kept for saturation for two hours. Then excess of API or drug is added to this

solution and shaken vigorously for 24hrs. Then kept aside for two hours for the layer

separation, when both the layers are separated they are collected carefully without mixing

by using the separating funnel. Finally, the separated layers are assayed by HPLC to

determine the concentration of drug in the each layer.

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3.4. 5.3 Enhancing solubility and stability of ORL

ORL is low water soluble and very hygroscopic drug and technically difficult to prepare

as tablets. For this reason, different strategies for enhancing the solubility and stability of

ORL were tried in the preformulation study. Among these methods, Complexation with

the β-cyclodextrin was found to be more effectively enhancing the solubility and

stability. As a result, ORL β-CD physical mixture and complex in different ratio were

made.

3.4. 5.4 Preparation of ORL β-cyclodextrin physical mixture and complex

A. Physical mixing

Accurately weighed quantity of ORL was mixed vigorously with β-CD in the

different molar ratios of 1:0.5, 1:1, 1:1.5 and 1:2 in the dry state. The mixtures is then

pressed through #60 sieve to have uniform size and stored in a desiccator.

B. ORL β-cyclodextrin inclusion complex by kneading method

The accurately weighed and passed through #60 quantity of ORL and β-CD in the

molar ratio of (1:0.5, 1:1, 1:1.5 and 1:2M), was put into a mortar with few drops of water-

alcohol (1:1) solution. The thick mass was vigorously kneaded to the paste consistency

for 1hour. The dry solid lump obtained is kept in the desiccator for 48h to remove the

moisture. The dried complex large aggloromates after drying were grounded and pressed

through sieve #60, and stored in a desiccator.

3.4. 5.5 Evaluation of the inclusion complexes by X-Ray Diffraction

X-Ray Diffraction (XRD) is one of the sophisticated methods used techniques

utilized for the solid state characteristics of drugs. Therefore samples of pure drug and β-

CD complex were analyzed by XRD. XRD is the one of the novel technique for the

physical characterization of crystallite state of a solid substance.

3.4. 5.6 Drug content estimation of ORL- β-CD complex

200 mg of ORL-β-cyclodextrin complex was weighed accurately and dissolved

200 ml volumetric flask and the volume was made with buffer of pH 6.8 phosphate

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buffer. Suitable dilutions are made by using pH 6.8 phosphate buffers. The amount of

drug present in the complex was analyzed by HPLC.

3.4. 5.7 Solubility determination of ORL and ORL β-CD complex

To determine the solubility of pure ORL, β-CD (PM) and β-CD complex in

distilled water. A well recognized procedure called as the standard shake flask method

was followed. In this procedure the excess quantity of the powder is taken in a 50ml

conical flask with a closure to this 20ml of water is added, and the resulting suspension is

shaken on a shaker bath (Remi) at 100 rpm for 48hr at room temperature. The solution is

first centrifuged and kept stationary for one hr then supernatant layer is filtered using a

the branded filter paper of 0.45µ and the filtrate solution is diluted suitably and the

amount of drug present is analyzed by HPLC.

3.4.6 Formulation Design and Compression of ORL Orodispersible Mini-tablets

(ORMTs):

The formulation of the orodispersible mini-tablets is one of the challenging

pharmaceutical dosage forms. Because the formulation scientist need to consider not

only the rapid disintegration and dissolution of the tablets with an eye on the stability of

the minitablets prepared. In addition to that the formulator also needs to consider the

platability of the developed orodispersible minitables solid dosage form. In the present

project for this reason after taking into consideration all these parameters the

formulation design of the orodispersible minitables was done by appropriately selecting

the novel co-processed excipients like, Pharmabrust-500, Pearlitol flash, Kolliphor P188

and Ludiflash. The preparation of the ORL orodispersible minitables was done by direct

compression method. The formulation design table and compressed orodispersible

minitables images are shown in the table no. 08 and figure no.18.

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Table-08 Formulation design of ORL Orodispersible Mini-tablets (ORMTs):

Ingredients ORMT-

1

(%)

ORMT-

2

(%)

ORMT-

3

(%)

ORMT-

4

(%)

ORMT--

5

(%)

ORMT--

6

(%)

ORMT--

7

(%)

ORMT--

8

(%)

ORMT--

9

(%)

OR-βCD [1:2M] 53 53 53 53 53 53 53 53 53

Pearlitol flash 20 30 40 -- -- -- -- -- --

Pharmabrust 500 -- -- -- 20 30 40 -- -- --

Ludiflash -- -- -- -- -- -- 20 30 40

D-Sorbitol 20 10 -- 20 10 -- 20 10 --

Kolliphor P188 02 02 02 02 02 02 02 02 02

Sucralose 02 02 02 02 02 02 02 02 02

Vanilla Flavour 01 01 01 01 01 01 01 01 01

Colloidal silicon

dioxide

01 01 01 01 01 01 01 01 01

Mg. stearate 01 01 01 01 01 01 01 01 01

* Each Formulation of ORMTs weighing 30mg contains 6mg of ORL.

3.4.6.1 Preparation of Orodispersible Mini-Tablets of ORL:

Weighed quantities of ORL-βCD Complex, and other excipients as shown in (Table 08),

were passed through a sieve #60 and mixed in the geometrical order in a plastic zip lock

ballooned pouch. Then, the lubricants magnesium stearate and colloidal silicone dioxide

were added and further mixed vigorously for ten minutes and compressed utilizing the

three milli meter multi-tip punches on nine station rotary tablet compression machine as

Shown in (Fig. no.18.

Fig. 18 Orodispersible Mini-Tablets of ORL

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3.4.7 Pre-Compression Evaluation of Powder / Granules:

Flow properties

• Angale of Rupose (AR)

• Balk Dencity (BD)

• Tappad Dencity (TD)

• Comprassibility Index (CI) &

• Hasner Ratio (HR)

a) AR is the maximum angle between the surfac of a pile of powder and the horizontale

plane. AR is one of the methods to determine the flow properties of solids so the rate

of flow of the mixture of powder can be known. The method of determining the AR

can be carried out by two methods.

b) In the first method the base is constant and the powder is passed through the funnel

fixed at a known height.

c) The second method is that where the base is fixed with a known diameter and the

powder pile is formed from the known distance of funnel.

The AR can be determined by using the formula given below

Base5.0

)h(Heighttan =α

Based on the AR values of any powders obtained, the powders can be categorized as

shown in the below table.

Table-09 The different

Flow property

Very Good

Good

Fair – aid not needed

Passable –

Poor – must

Very poor

Very, very poor

b) Bulk density and Tapped density

Bulk density of a powder is the density of the powder that is the weight in

grams per milli liter volume. It is generally evaluated by taking the loose powder

with voids in a measuring cylinder of known length. Prior to placing in the

measuring glass cylinder or any other measurable cylinder it is must to pass

through the appropriate sieve and t

It is given as

Where BD is bulk density

M is mass of powder sample

Vo is volume occupied by untapped powder sample

Then the known weight is taken and placed in the graduated cylinder and

the volume is noted prior to tapping and after tapping. Tapped density is the

density of the powder without the voids which are removed by tapping the

The different range of powder flow categorized based on angle of repose.

Flow property Angle of repose (°)

Very Good 26 – 30

30 – 35

aid not needed 35 – 40

may resist the flow 40 – 45

must required to vibrate 45 – 55

55 - 65

Very, very poor > 65

b) Bulk density and Tapped density


liter volume. It is generally evaluated by taking the loose powder



through the appropriate sieve and the place in a graduated cylinder.

Where BD is bulk density

M is mass of powder sample

is volume occupied by untapped powder sample




116 | P a g e

of powder flow categorized based on angle of repose.

Angle of repose (°)


liter volume. It is generally evaluated by taking the loose powder



he place in a graduated cylinder.




graduated cylinder. To find the t

in the placed in the graduated cylinder and the final volume after tapping is

observed.

Where, TD is tapped density

M mass of powder sample

Vf is the final tapped volume otherwise repeat in increments of

difference between succeeding measurements is less than 2%.

c) Hausner Ratio and compressibility Index

Both these index are the measure of powder flow property.

and Hausner ratio are given as follows

Where V0, Vf are initial volume and final tapped volume

ρbulk, ρtapped are initial bulk density and final tapped density

The general maximum and minimum p

Hausner ratio and compressibi

graduated cylinder. To find the tapped density the initial volume of the poweder


Where, TD is tapped density

M mass of powder sample

is the final tapped volume otherwise repeat in increments of 500 taps until the

difference between succeeding measurements is less than 2%. It is given as

c) Hausner Ratio and compressibility Index

Both these index are the measure of powder flow property. Compressibility index

ratio are given as follows

are initial volume and final tapped volume

are initial bulk density and final tapped density

maximum and minimum powder flow range categorization based on

Hausner ratio and compressibility index is given in table 10.

117 | P a g e

apped density the initial volume of the poweder


500 taps until the

It is given as

Compressibility index

range categorization based on

118 | P a g e

Table-10 Maximum and minimum powder flow range categorization based on HR

and CI index.

Compressibility Index (%) Hausner

ratio Flow character

≤ 10 1.00 – 1.11 Have excellent

flow

> 35 > 1.50 Have very poor

flow

3.4.8 Post-compression Evaluation of ORL Orodispersible Mini-tablets (ORMTs:

The various quality control tests, that are need to be carried out as per the standard

monographs are:

3.4.8.1 Thickness:

In the physical evaluation of the pharmaceutical solid dosage form tablets thickness has

both visual impact and also it is inversely proportional to the hardness of the tablets.

Generally, the thickness of the tablets is measured using screw gauge or vanier caliper.

The thickness of ten tablets from each formulation was determined and the average results

are tabulated.

3.4.8.2 Hardness

The hardness of the tablets is indicator of its crushing strength or the force required to

break it. Hardness will not only affect the overall integrity of the tablets but also it can

affect the disintegration and dissolution or the bioavailability of pharmaceutical tablets.

The Dr Schleuniger Pharmatron 8M hardness tester is used to determine the tablet

hardness. The force required to break the tablet was displayed in kilograms and

recorded. Hardness of ten tablets was determined and the average results are tabulated.

3.4.8.3 Friability test:

Friability of tablets is one of the important quality control tests of tablets and it is

determined to know whether the prepared tablets can withstand the impacts and attritions

that occurs during the handling, processing and transportation.

batch are examined by taking the initial weight and placed in the Roche Fribilator. The

equipment is run for four minutes running at twenty five

tablets are removed from the friabilitor

and percent friability is found by

To determine the percentage friability the

Where W1 = Weight of tablets before

W2 = Weight of tablets after

3.4.8.4 Weight Variation Test:

Twenty tablets from each batch a

and collectively on a digital weighting balance. The average weight of one tablet was

determined from the collective weight.

tablets will pass the quality control test when the

standard limit.

The acceptable limits of the weight variation of the pharmaceutical tablets are shown in

the table no. 11.

Table-11 Weight variation Limits

Tablet Weight

130

that occurs during the handling, processing and transportation. Ten tablets from each


four minutes running at twenty five revolutions per minute. The

removed from the friabilitor, and the dust attached is removed

found by.

To determine the percentage friability the following formula is used:

Weight of tablets before the tablets placed in friabilator

Weight of tablets after the tablets removed from friabilator

iation Test:

from each batch are taken and their weight was determined individually


determined from the collective weight. As per the monograph guidelines the prepared

tablets will pass the quality control test when the not more than two tablets will cross the


Weight variation Limits as per the monograph (I.P.)

Tablet Weight %Weight Variation

<130 10

130-324 7.5

>324 5

119 | P a g e

Ten tablets from each


revolutions per minute. The

and the dust attached is removed and reweighed

termined individually


As per the monograph guidelines the prepared

not more than two tablets will cross the


(I.P.)

% Tablet Weight

3.4.8.5 Wetting Time Evaluation:

In a small petri dish of

color solution (containing a pinch of

place the mini-tablet at the centre and the time required to

the tablet or complete wetting time of the tablet is noted down.

3.4.8.6 In vitro Disintegration test:

Following the standard reference, a modification in the conventional method was made to

determine the disintegration time of the mini

in which the mesh screen

disintegration time, ten ml of 6.8

six ml of the buffer was below the sieve and

on the sieve and the whole

of formulation six tablets disintegration time was determined

3.4.8.7 Uniformity of drug content

Taking fifty mini-tablets from each

with the pestle. The crushed p

was weighed and put in to a 100 ml V.F,

shaken on a cyclo mixture first and then sonicated for

is dissolved methanol is added to make up the volume. Filter this sol

branded with 0.45µ filter paper and filtrate after the centrifugation supernatant liquid is

taken and diluted with methanol and

Tablet Weight Deviation

Wetting Time Evaluation:

petri dish of twenty centimeter diameter pour twenty milliliter of aqueous

(containing a pinch of eosin dissolved). In this color solution carefully

tablet at the centre and the time required to absorb the colo

the tablet or complete wetting time of the tablet is noted down.

Disintegration test:

reference, a modification in the conventional method was made to

determine the disintegration time of the mini-tablets. A glass cylindrical beaker was used

mesh screen of #10 size was placed in the middle. To

ml of 6.8 pH buffer, was poured in the beaker in such a way that

ml of the buffer was below the sieve and four ml above the sieve. Tablet was placed

on the sieve and the whole equipment was then placed on a shaker bath.

mulation six tablets disintegration time was determined.

Uniformity of drug content

tablets from each batch of formulation in a glass mortar

The crushed powder of mini-tablets that is equivalent to

n to a 100 ml V.F, adding little around 20 ml of methanol. This is

shaken on a cyclo mixture first and then sonicated for half hour. When complete powder

is dissolved methanol is added to make up the volume. Filter this sol

filter paper and filtrate after the centrifugation supernatant liquid is

taken and diluted with methanol and was analyzed by HPLC.

120 | P a g e

milliliter of aqueous

solution carefully

the color solution into

reference, a modification in the conventional method was made to

cylindrical beaker was used

was placed in the middle. To know the

in the beaker in such a way that

ml above the sieve. Tablet was placed

. From each batch

formulation in a glass mortar and powdered

equivalent to one mini-tablet

adding little around 20 ml of methanol. This is

. When complete powder

is dissolved methanol is added to make up the volume. Filter this solution using the

filter paper and filtrate after the centrifugation supernatant liquid is

121 | P a g e

3.4.8.8 In vitro dissolution studies

The release of the drug by in-vitro dissolution test was carried out using the paddle

apparatus officially called as the USP II apparatus. The test operation was done following

the standard reference for ORL; the 3% w/v aqueous solution sodium lauryl sulfate

containing the 0.5% of sodium chloride that was adjusted to pH6 with phosphoric acid

was the dissolution medium. Five ml of filtered solution was withdrawn manually using

disc filter syringe, at the specified time intervals and fives ml of fresh dissolution medium

was replaced. The collected samples of solution were filtered again with 0.45µ branded

filter paper and the filtrate after making the suitable dilution was assayed by HPLC

(Taylor et al., 2010).

3.4.8.9 Taste Evaluation Studies

a) Participants

In this project work the optimization of the taste was very crucial aspect. And therefore

the taste evaluation studies were carried out with the help of five volunteers. All the

volunteers participated in the taste evaluation were requested to taste the optimised

product thrice once a day continuously for three days.

a) Methodology of Evaluation:

Each volunteer has evaluated the taste of optimized formulation thrice. Each volunteer

cleansed their palate with water and the optimised orodispersible ORMTs were kept for

10-15seconds over the tongue applying some pressure and then disgorged completely and

rinsed out with water. The taste, after-taste sensation and other effects were evaluated on

a scale of 1±5. The taste scale was the immediate facial expression followed by the

responses upon tasting the chewable ORMTs was observed and score was given.

Volunteers were asked to give oral response after spitting the remnants of the tablets and

rinsing. Then the responses to the queries related to the taste of the chewable product in

the study were noted (Robert Cohen et al., 2009).

122 | P a g e

3.4.9 A short term stability study of the optimized ORMTs:

A short term stability testing was carried out to determine the stability of the optimised

formulation under the influence of stress condition of temperature and humidity for a

stipulated period of three months. The optimised samples of the formulations were placed

under the controlled temperature and humidity cabinet. As specified by the Tripartite

guideline of ICH, 2003 an accelerated short term stability study adopting 75% relative

humidity at a temperature of 40°C with the variation of five percent for humidity and two

percent for the temperature was carried out.

In order to study the stability of the optimized formulation, the representative samples

were sealed in aluminum foil and stored at room temperature conditions (silica gel to

control moisture content) and in a controlled temperature cabinet at 40°C (75% RH)

(silica gel to control moisture content). The physicochemical properties of these samples

were evaluated after three months (Tripartite guideline of ICH, 2003).

Table-12 Stability studies, storage conditions and duration of study (Tripartite

guideline of ICH, 2003).

Study Storage conditions Minimum time Period

Long –term 25°C and 60% RH Twelve months

Intermediate 30°C and 65% RH Six months

Short term 40°C and 75% RH Six months

123 | P a g e

3.5 RESULTS AND DISCUSSIONS

3.5.1 Pre-Formulation Studies Results:

3.5.1.1 The results of Melting Point (M.P) estimation:

Melting point of ORL was found to be in with range as per literature and readings were

given below table.

Table-13 Melting point reading of Pure ORL

Name of Drug Observed M.P Reference M.P

ORL 46ºC 45ºC-48ºC

ORL is a low melting point drug and it is hygroscopic in nature (Effat, S et al., 2007).

The melting point was determined in the pre-formulation study to ensure the purity of the

drug. The M.P of the ORL was found to be in the range of reference M.P.

3.5.1.2 The results of Solubility Studies:

Solubility test for the ORL was conducted in distilled water, 3% SLS in water and

methanol.

Table-14 Solubility studies of Pure ORL in different Solvents:

S.No Solvent Solubility(mg/ml) Reference(mg/ml)

1. Water 1.18±0.13 1.34

2. Methanol 25.78±1.03 30.32

3. Water+3% SLS 93.34±1.34 100.23

*The values are presented as the mean ± SD, n=3

A complete knowledge of the drug substance during the preliminary preformulation

studies is very crucial for the development of any pharmaceutical product. The maximum

upto seventy percent of the drugs are poorly water soluble and belongs to the BCS class-

II system. For this reason the most widely employed experimental method for the

estimation of solubility is carried out by gold standard shake flask method (Donnell and

Williams 2012).

124 | P a g e

The solubility study of ORL was performed in three different solvents i.e., water,

methanol and water + 3% SLS. The solubility results of ORL as shown in the table-14,

indicate that the drug ORL is more soluble in the aqueous solution containing 3% of SLS.

ORL is a very low aqueous soluble drug and therefore has very low bioavailability. But

this API does not require high bioavailability as it shows action locally. However,

irrespective of the site of action a high solubility of drug is recommended for the

maximum and rapid libration of the drug from the dosage form or drug delivery system.

Therefore water + 3% SLS is recommended and used as the dissolution medium (A.

Dolenc et al., 2010).

3.5.1.3 The results of Partition Coefficient Study:

Table-15 Partition Coefficient Studies of drugs ORL

Name of Drug Observed LogP Reference LogP

ORL 7.54±1.04 8.11


ORL is a BCS class-II drug and therefore high permeability but negligible aqueous

solubility. It has a high Log P value indicating the high permeability through the

biological membrane. The partition coefficient study taking the octanol and water is the

standard method to determine the log P or partition coefficient of particular drug. When

the partition coefficient study of ORL was performed the logP value was comparable to

the reference log P value of the ORL as shown in the table-15.

3.5.1.4 Drug-Excipients Compatibility Studies:

In the formulation of any dosage form drug-excipients and the excipients-excipients

compatibility assessment is one of the prime requirements during the preformulation

study. In this project the drug and excipients compatibility study was carried out by IR

spectroscopy (H. K Chan, 2007)

125 | P a g e

Table-16 Drug excipients compatibility results

Drug Name Drug-Excipients combination Results

ORL API alone Complies

API+Excipients Complies

The FTIR spectrum of the pure ORL and VNF were compared with standard spectrum of

ORL and VNF, there is no deviation of functional groups. Excipients compatibility

studies were carried out by comparing by overlapping the FTIR spectrum of pure drug

and the FTIR spectrum of formulations. The individual IR spectrum of pure drugs and

formulations were found to be similar, and there is compatibility between the active and

nonactive ingredients as shown in the figures 19-21.

Fig. 19 FTIR spectrum of ORL (Pure drug)

126 | P a g e

Fig. 20 IR Spectra of ORL with Excipients

The FT-IR spectra of the drugs and drugs in combination with other excipients were

recorded with ABB Bomen Series spectrophotometer over the region of 400 – 4000 cm-1

by adopting Potassium bromide disc containing the samples one percent prepared prior to

IR analysis at Sipra Labs, Hyderabad. Pure drug of ORL complies with the reference

samples and the combination of API with different excipients show no deviation from the

pure drug. Hence there was no compatibility problem between API and excipients. FTIR

spectrums of samples are shown in the above figures.

3.5.1.5 X-ray Diffraction Study of Pure ORL and ORL- β-CD complex

Changes in the polymorphic forms are possible during the processing and storage of the

dosage form. These changes may lead to instability, changes in the solubility and

dissolution rate and could cause the problems of the finished dosage form like changes in

the physical appearance, mechanical strength, disintegration and dissolution rate and the

overall bioavailability and efficacy.

X-ray diffraction analysis is widely used to evaluate the polymorphic changes that may

take place in the blends of formulations (Abu Serajuddin T. M, et al., 1999).

127 | P a g e

Fig. 21 X-ray Diffractograms of (a) ORL Pure (b) ORL-β-CD (1:2) complex

In the above figure X-ray diffraction analysis of pure ORL and the ORL-β-CD complex

is shown. From the X-ray diffractograms it is indicated that there is no change in the solid

state form of pure ORL and the ORL in the β-CD complex.

128 | P a g e

3.5.2 ANALYTICAL METHODS DEVELOPMENT

3.5.2.1 Determination of λmax of ORL by UV Spectroscopy:

UV scan was taken for ORL solution (100µg/ml) between 200- 400 nm. The UV

spectrum shown in figure 22 indicates that the peak (λmax) was obtained at 210 nm. In

the literature, 205-210 nm wavelengths were reported. Wavelength of 210 nm was

selected for the analytical work of ORL.

Fig. 22 UV-spectrum of ORL

i. Standard Graph of ORL in methanol:

Standard curve of was obtained by taking the UV reading of concentrations versus

absorbance and plotting graphically. The coefficient of regresion equation was obtained.

Bear-Lambart’s law obeyed in the range from 10 to 160µg/ml. The regresion coefficient

was found to be 0.999 both in methanol and water + 3% SLS respectively. The regresion

coefficient was used for the calculation of ORL content in mini-tablets and in-vitro

release studies.

210 nm

Table-17 Standard graph data of ORL in Methanol

S.NO Concentration(µg/ml)

1

2

3

4

5

6

7

8

9

10

*The values are presented

Fig. 23 Standard graph for ORL in Methanol

A

B

S

Standard graph data of ORL in Methanol

Concentration(µg/ml) Absorbance Std. Deviation

20 0.021 ±0.0043

40 0.052 ±0.0054

60 0.093 ±0.0047

80 0.135 ±0.0023

100 0.182 ±0.0035

120 0.223 ±0.0012

140 0.256 ±0.0023

160 0.302 ±0.0043

180 0.341 ±0.0021

200 0.385 ±0.0056

are presented as the mean ± SD, n=3

Standard graph for ORL in Methanol

129 | P a g e

Std. Deviation

±0.0043

±0.0054

±0.0047

±0.0023

±0.0035

±0.0012

±0.0023

±0.0043

±0.0021

±0.0056

Table-18 Standard graph data of ORL in Water + 3%


1

2

3

4

5

6

7

8

9

10


Fig. 24 Standard Graph of ORL in Water + 3% SLS

A

B

S

Standard graph data of ORL in Water + 3% SLS

Concentration(µg/ml) Absorbance Std. Deviation

20 0.024 ±0.0047

40 0.061 ±0.0058

60 0.097 ±0.0054

80 0.137 ±0.0023

100 0.184 ±0.0039

120 0.227 ±0.0021

140 0.269 ±0.0023

160 0.302 ±0.0034

180 0.347 ±0.0054

200 0.381 ±0.0054


Standard Graph of ORL in Water + 3% SLS

Conc. (µg/ml)

130 | P a g e

Std. Deviation

±0.0047

±0.0058

±0.0054

±0.0023

±0.0039

±0.0021

±0.0023

±0.0034

±0.0054

±0.0054

131 | P a g e

3.5.2.2 HPLC Method Development by reverse phase for the estimation of ORL

A HPLC method for the ORL was developed and ORL peak is shown in the below

chromatograph. The ORL was eluted at 9.49minutes shown in the below figure.

Fig. 25 HPLC Chromatograph of ORL.

3.5.2.3 Standard Graph of ORL by HPLC:

Standard graph was plotted by taking the concentration and peak area. Regresion

equation was obtained. Linearity was found to be 20 to 200µg/ml. The coefficient of

regresion was satisfactorily high (0.999). The regression equation was used for the

estimation of ORL in the mini-tablets and in-vitro release studies. The results are given in

the table-19

Table-19 Standard graph data of ORL by HPLC


1

2

3

4

5

6

7

8

9

10

11

12

13


Fig. 26 ORL Standard graph by HPLC

P

E

A

K

A

R

E

A

Standard graph data of ORL by HPLC

Concentration(µg/ml) Peak Area Std. Deviation

1 1670 ±0.0034

5 8352 ±0.0058

10 13684 ±0.0042

20 31522 ±0.0034

40 62372 ±0.0054

60 97587 ±0.0034

80 130500 ±0.0053

100 162919 ±0.0051

120 195238 ±0.0058

140 227843 ±0.0054

160 257843 ±0.0033

180 292190 ±0.0042

200 322111 ±0.0054


ORL Standard graph by HPLC

Conc. (µg/ml)

132 | P a g e

Std. Deviation

±0.0034

±0.0058

±0.0042

±0.0034

±0.0054

±0.0034

±0.0053

±0.0051

±0.0058

±0.0054

±0.0033

±0.0042

±0.0054

3.5.2.4 Solubility study results of pure ORL and OR

Fig. 27 Solubility study results of pure ORL and OR

complexes.

Complexation of drug is one of the many strategies to effectively enhance the

physicochemical properties of pharmaceutical compounds. Cyclodextrins especially the

β-cyclodextrins are the good examples inclusion complexes formed compounds. Drug

complex with β-cyclodextrins

(Gerold Mosher et al., 2007).

ORL is a very low aqueous soluble hydrophobic drug and belongs to the BCS class

system (A. Dolenc et al.,

complexation with β-cyclodextrin in different ratio was tried and the solubility profile of

the pure ORL and ORL-β

27. ORL-βCD complex in (1:2M)

solubility from 1.2 mg/ml to 8.9

the ratio of (1:2M), as it was enhancing the solubility of the ORL and also found suitable

to incorporate in the ORL orodispersible mini

coprocessed excipients.

1.2

0

2

4

6

8

10

ORL-Pure drug ORL

mg

/ m

l

ORL-βCD Physical Mixture (mg/ml)

Solubility study results of pure ORL and ORL-βCD complex

Solubility study results of pure ORL and ORL-βCD Ph. Mix and OR



are the good examples inclusion complexes formed compounds. Drug

cyclodextrins depends on the fraction of drug that gets complexed

Gerold Mosher et al., 2007).

ORL is a very low aqueous soluble hydrophobic drug and belongs to the BCS class

et al., 2010). To enhance the solubility and stability of the ORL,

cyclodextrin in different ratio was tried and the solubility profile of

βCD physical mixtures and the complex are shown in the

complex in (1:2M) was found more effective and was in

solubility from 1.2 mg/ml to 8.9 mg/ml. The ORL-βCD Complexation was confined to


to incorporate in the ORL orodispersible mini-tablets formulations using the novel

1.28 1.351.73

2.14

4.63

6.24

ORLβCD(1:0.5) ORLβCD(1:1) ORLβCD(1:1.5)

CD Physical Mixture (mg/ml) ORL-βCD Complex (mg/ml)

133 | P a g e

complex

CD Ph. Mix and OR-βCD



are the good examples inclusion complexes formed compounds. Drug

depends on the fraction of drug that gets complexed

ORL is a very low aqueous soluble hydrophobic drug and belongs to the BCS class-II

2010). To enhance the solubility and stability of the ORL,

cyclodextrin in different ratio was tried and the solubility profile of

physical mixtures and the complex are shown in the figure

was found more effective and was increasing the

Complexation was confined to


tablets formulations using the novel

1.84

8.9

ORLβCD(1:2)

134 | P a g e

3.5.3 Pre-Compression Evaluations Results

Table-20 Pre-Compression Evaluations of lubricated blend of formulations

Formulations A.R B.D g/ml T.D g/ml C.I (%) H.R

ORMT1 41.260 0.543 0.749 27.50 1.38

ORMT2 36.530 0.529 0.689 23.22 1.30

ORMT3 31.240 0.537 0.645 16.74 1.20

ORMT4 33.260 0.539 0.683 21.08 1.27

ORMT5 34.720 0.549 0.679 19.15 1.24

ORMT6 30.280 0.563 0.653 13.78 1.16

ORMT7 32.250 0.561 0.701 19.97 1.25

ORMT8 31.740 0.576 0.693 16.88 1.20

ORMT9 31.230 0.526 0.818 12.81 1.15

Powder sufficiently flowing characteristics are one of the major requirement for the

successful manufacture or development of solid dosage form. Another critical step in the

manufacture of all solid dosage forms is the processing of blending or mixing the powder

is carried out. In assessing the quality of the mixture blend, the method of sampling is

more important (Peter Davies 2009).

Prior to compression of the mini-tablets the formulations powder blends was passed

through the sieve#60 and then mixed well and further blended after adding the lubricants.

The lubricated blend of all the nine formulations (ORMTs1-9) were evaluated for the

different flow properties tests and the results are shown in the table-20.

3.5.3 Post-compression Evaluation of the Compressed ORMTs:

In the post-compression ORL ORMTs compressed mini-tablets evaluations, all the

evaluations like weight differences, improper friability, less or more hardness, less or

more thickness, less or more wetting time, less or more disintegration time and less or

more drug content uniformity quality control tests were performed and the results are

shown in the table-21.

135 | P a g e

Table-21 ORL ORMTs Compressed Mini-Tablets Evaluations

Formuln

. Code

Weight

Variation

(n=20)

Friability

(%)

(n=10)

Hardness

(Kg/cm²)

(n=5)

Thickness

(mm)

(n=5)

Content

Uniformity

(%)

Wetting

time

(Secs.)

Disintegration

test

(Secs.)

ORMT1 30.45±0.15 0.15±0.10 2.10±0.30 3.44±0.01 100.92±0.64 38±2.08 115±0.32

ORMT 2 29.18±0.28 0.07±0.09 2.20±0.10 3.34±0.01 99.59±0.20 33±2.07 91±0.23

ORMT 3 29.82±0.41 0.13±0.08 2.40±0.20 3.23±0.02 99.14±0.31 30±2.09 72±0.34

ORMT 4 30.27±0.32 0.13±0.07 2.12±0.20 3.56±0.04 99.87±0.48 40±1.10 112±0.12

ORMT 5 30.58±0.56 0.09±0.06 2.30±0.30 3.45±0.01 100.14±0.20 36±1.00 88±0.33

ORMT 6 31.23±0.45 0.15±0.046 2.6±0.14 3.24±0.03 99.87±0.80 32±1.13 60±0.41

ORMT 7 31.19±0.25 0.12±0.022 2.5±0.13 3.42±0.01 99.55±0.69 35±1.08 94±0.37

ORMT 8 31.36±0.92 0.16±0.058 2.9±0.14 3.23±0.04 99.73±0.34 32±2.10 76±0.58

ORMT 9 30.54±0.45 0.11±0.078 2.5±0.15 3.26±0.05 100.32±0.23 25±1.11 55±0.43


Mini-tablets proven to have many advantages compared to pellets and granules for

example, uniform in size and shape with no multiple coating. If required mini-tablets can

be coated with polymeric film to enhance the stability and require less coating material

because of uniform size and shape with robust mechanical properties (Munday, 1994 and

Bredenberg et al., 2003). In the present project also all the ORL ORMTs formulations (1-

9) compressed mini-tablets physico-chemical properties evaluated have been found to

within the standard limits. And on the basis of results obtained the ORMT-9 formulation

was seem to be the optimized formulation. Further the in-vitro dessolution study of all the

ORMTs formulations was carried out and the results obtained are shown in the table-22

and figure 28.

Ultimately based on the dessolution study results the formulation ORMT-9 was chosen as

the optimized formulation.

3.5.4.1 Dissolution Profile of ORMT Formulations (1

Table-22 ORL ORMT

Marketed capsule.

Time

(min

)

ORMT

-1

ORMT

-2

ORMT

-3

0 0 0

1 24.56 29.87 32.43

2 40.2 41.25 42.15

6 65.25 70.58 66.63

8 80.54 84.25 76.46

10 94.54 97.34 101.61

15 100.43 99.86 101.23

30 101.22 101.32 102.4

Fig. 28 ORL ORMTs Dissolution profile of formulations

Dissolution Profile of ORMT Formulations (1-9):

ORMTs Dissolution profile of formulations ORMT

Marketed capsule.

ORMT ORMT

-4

ORMT

-5

ORMT

-6

ORMT

-7

ORMT

-8

0 0 0 0 0 0

32.43 27.98 27.35 28.42 29.54 29.76

42.15 41.25 42.75 44.25 45.25 42.25

66.63 65.58 68.58 70.28 70.18 70.58

76.46 72.25 84.25 86.27 87.25 87.25

101.61 90.54 93.34 97.64 96.39 97.34

101.23 96.78 96.34 99.76 99.89 99.67

102.4 99.45 100.27 101.54 101.25 100.45

s Dissolution profile of formulations ORMT (1-9)

136 | P a g e

ORMT (1-9) and

ORMT

-9

Marketed

-Capsule

0 0

25.22 1.46

39.93 4.54

55.71 9.54

70.15 13.25

86.18 15.89

98.76 26.47

101.12 39.53

137 | P a g e

In a study conducted by (Stoltenberg et al., 2011) in which fast disintegrating mini tablets

prepared using the novel coprocessed excipient ludiflash were found to be stable with

good friability and hardness and were shown to be releasing the drug rapidly. Similarly in

our project the optimized formulation containing the forty percent of ludiflash was found

to be disintegrating in less than a minute with nearly ninty percent of the drug release in

the initial ten minutes.

3.5.4.2 Optimised ORMT-9 Comparison with the Marketed IR Caps.

The optimized formulation ORMT-9 was compared with the existing marketed capsules

and the results are shown in the table-23, figures 29 and 30.

Table-23 Comparative Assays of ORL (ORMT-9) and Marketed IR Caps.

S.No Drug Name Peak Area Rt Recovery (%)

1. ORL Caps 162427.27 9.52 99.80

2. ORMT-9 161998.32 9.51 98.65

In a comparative study the optimized formulation (ORMT-9) with that of the marketed

capsule drug content was almost similar shown in the figure 29.

Fig. 29 HPLC Chromatograph of (ORMT-9) and Marketed ORL capsule.

In the in-vitro drug release study, the optimized formulation was found to be librating the

drug as much as three times rapidly in comparision to the marketed capsule as

in the figure 30. The complete drug release of ORMT

minutes.

Fig. 30 Dissolution profile of Optimized formulation (ORMT

capsule.

This difference in the dissolution rate can be rationalized in many ways. First in the

(ORMT-9), increase in the solubility and dissolution rate

complexing the ORL with the

incorporation of ludiflash and Kolliphor P188 the very effective novel coprocessed

excipients in the optimised formulation. Lastly, the delineating fact could be the mini

tablets small size itself that has enhanced

optimized formulation (ORMT

3.5.5 Taste Evaluation of the Optimized formulation

The overall patient acceptability based on the

disintegrating tablets especially the taste masking is

(Nakano Y et al., 2013). ORL has no bad taste, but it is very hygroscopic and slight waxy

vitro drug release study, the optimized formulation was found to be librating the

s much as three times rapidly in comparision to the marketed capsule as

The complete drug release of ORMT-9 was happened in less than ten

Dissolution profile of Optimized formulation (ORMT-9) and Markete


9), increase in the solubility and dissolution rate of ORL was done by

complexing the ORL with the β-CD suitable molar ratios. Then second, could be the


excipients in the optimised formulation. Lastly, the delineating fact could be the mini

tablets small size itself that has enhanced the dissolution rate. For this reason the

optimized formulation (ORMT-9) was comparatively releasing the drug faster.

Taste Evaluation of the Optimized formulation (ORMT-9) Results:

patient acceptability based on the palatability, of the chewable

especially the taste masking is very important in the development

Nakano Y et al., 2013). ORL has no bad taste, but it is very hygroscopic and slight waxy

138 | P a g e

vitro drug release study, the optimized formulation was found to be librating the

s much as three times rapidly in comparision to the marketed capsule as as shown

9 was happened in less than ten

9) and Marketed ORL


ORL was done by

molar ratios. Then second, could be the


excipients in the optimised formulation. Lastly, the delineating fact could be the mini-

the dissolution rate. For this reason the

9) was comparatively releasing the drug faster.

Results:

of the chewable orally

in the development

Nakano Y et al., 2013). ORL has no bad taste, but it is very hygroscopic and slight waxy

hydrophobic drug. Therefore to enhance the stability

cyclodextrins in different molar ratios was tried and the ORL and

found to be more feasible in enhancing both the stability and solubility of the ORL

therefore chosen for the formulation of ORMTs.

Fig. 31 Taste Evaluation of

The taste evaluation studies were carried out with the help of five

volunteers participated in the taste evaluation

product thrice once a day continuously for three days.

(ORMT-9) were kept for 10

disgorged completely and rinsed out with water. The taste, after

effects were evaluated on a scale of 1±5

obtained are depicted in the figure 31.

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Volunteer1

Ta

ste

Sca

le o

f F

ive

hydrophobic drug. Therefore to enhance the stability and solubility Complexation with

cyclodextrins in different molar ratios was tried and the ORL and β-CD

found to be more feasible in enhancing both the stability and solubility of the ORL

therefore chosen for the formulation of ORMTs.

Taste Evaluation of Optimized Formulation (ORMT-9), on a scale of five

The taste evaluation studies were carried out with the help of five volunteers

participated in the taste evaluation were requested to taste the optimised

product thrice once a day continuously for three days. The optimized formulation

9) were kept for 10-15seconds over the tongue applying some pressure and then

tely and rinsed out with water. The taste, after-taste sensation and other

effects were evaluated on a scale of 1±5 (Robert Cohen et al., 2009).

obtained are depicted in the figure 31.

Volunteer1 Volunteer2 Volunteer3 Volunteer4 Volunteer5

139 | P a g e

and solubility Complexation with β-

(1;2M) ratio was

found to be more feasible in enhancing both the stability and solubility of the ORL and

), on a scale of five

volunteers. All the

were requested to taste the optimised

The optimized formulation

15seconds over the tongue applying some pressure and then

taste sensation and other

et al., 2009). The results

3.5.6 Application of Different Kinetic Models to the

(ORMT-9) and Marketed Capsule

The different drug release kinetics of optimized formulations of ORL ORMT

order, First order, Higuchi and Hixson

constants are shown below.

3.5.6.1 Application of Zero order Model

Marketed Capsule

Fig. 32 Zero order release kinetics of Optimized ORL

marketed formulation

3.5.6.2 Application of First order Model

and Marketed Capsule

Application of Different Kinetic Models to the In-Vitro Drug Release of

9) and Marketed Capsule

The different drug release kinetics of optimized formulations of ORL ORMT

order, First order, Higuchi and Hixson-crowell models. The values of R

constants are shown below.

.1 Application of Zero order Model to the In-Vitro Drug Release of (

Zero order release kinetics of Optimized ORL ORMT-9 and

marketed formulation.

.2 Application of First order Model to the In-Vitro Drug Libration

140 | P a g e

Vitro Drug Release of

The different drug release kinetics of optimized formulations of ORL ORMT-9 as Zero

crowell models. The values of R2 and release

Vitro Drug Release of (ORMT-9) and

Vitro Drug Libration of (ORMT-9)

Fig. 33 First order release kinetics of Optimized ORL

Marketed formulation.

3.5.6.3 Application of Higuchi Model

Marketed Capsule

Fig. 34 Higuchi release kinetics of Optimized ORL

Marketed formulation.

First order release kinetics of Optimized ORL ORMT-

.3 Application of Higuchi Model to the In-Vitro Drug Release of (ORMT

Higuchi release kinetics of Optimized ORL ORMT

141 | P a g e

-9 and


ORMT-9 and

3.5.6.4 Application of Zero order Model

Marketed Capsule

Fig. 35 Hixson-Crowell release kinetics of Optimized ORL

formulation.

3.5.7 Stability Study of the Optimized

Table-24 Stability Study of the Optimised Formulation (

Parameters 30 days

Physical

Appearance

No Change

Weight Variation

(mg)

30.55±0.52

Hardness

(Kg/cm2)

2.6±0.42

Friability (%) 0.17±0.13

.4 Application of Zero order Model to the In-Vitro Drug Release of (

Crowell release kinetics of Optimized ORL ORMT

Stability Study of the Optimized Formulation (ORMT-9):

Stability Study of the Optimised Formulation (ORMT-9):

30 days After 60 days After 90 days After

No Change No Change No Change

30.55±0.52 29.48±0.65 29.32±0.79

2.6±0.42 2.50±0.38 2.40±0.51

0.17±0.13 0.18±0.25 0.19±0.23

142 | P a g e


ORMT-9 and Marketed

After

143 | P a g e

Drug Content

(%)

99.67±0.82 98.43±0.74 97.85±0.46

Disintegration

Time (Secs.)

55±0.41 54±1.02 53±1.21

The Stability study of the optimised formulation (ORMT-9) was carried out for 90 days,

following the short term accelerated stability testing ICH guidelines. The short term

stability study protocol, 40°C±2°C/75%RH±5% RH was followed (Tripartite guideline,

ICH 2003). The optimised formulation (ORMT-9) has shown no changes in the physical

appearance and physico chemical characteristics. There were very slight changes in all

the physical and chemical test parameters evaluated and more importantly uniformity of

drug content and disintigration test performed during the stability study evaluated at an

interval of thirty days. The results of short term accelerated stability study all the results

shown in the table above were within the acceptable limits.

144 | P a g e

3.6 CONCLUSION:

Obesity is the latest and rapidly growing epidemic and it ranks fifth as risk factor for the

deaths worldwide. In the present scenario, there should have been many

pharmacotherapies for the treatment of obesity. But at present ORL at present the only

US registered drug for the management of obesity for longer duration (Kakkar and

Dahiya 2015). ORL is a locally acting gastrointestinal lipase blocker used for the

reducing the weight in obese people. Lipase is the enzyme produced in the GIT and is

required for the digestion of various fats and triglycerides. ORL is capable of reducing

the weight upto five kilograms within a short period when recommended dose is used

(Anne Ballinger et al., 2002). But, ORL is available commercially in 60mg and 120mg

dose only as capsule dosage form (Colon-Gonzalez F et al., 2013). The parpose of this

project was to prepare Orodispersible mini-tablets of ORL (ORMTs) that can disintegrate

within a minute upon coming in contact with the aqueous fluid to enhance the patient

compliance and the efficacy. In the preformulation work purity of the drug ORL was

confirmed. There was no compatibility contradiction between the active and nonactive

substances confirmed by FTIR. The liquid charomatogrphic method is devlaped and

vaildated utilizing the reverse phase mobile liquid running at flow of 1.5ml for twelve

minutes and the retention time was found to be at 9.4 minutes. In the solubility

enhancement of ORL complexed with β-CD in one is to two molar ratio was found more

beneficial and was increasing the solubility from 1.91± 0.171 mg/ml to 8.81± 0.261

mg/ml. The crystalline state of Orlistat pure and Orlistat-β-CD complex is characterized

by the XRD and no change in the spectrum was found.

Then in the formulation this PDF nine trials were carried out using different co-processed

excipients and excipients. Pre and post compression evaluation of all the formulation was

done. All the valued were found to be within the standard limit. Based upon the results

obtained the formulation (ORMT-9), which was prepared using ludiflash nearly forty

percent was found to be disintegrating rapidly and releasing the ORL at regular intervals

and therefore this formulation was considered as the optimized formulation of ORMTs.

Further the optimised formulation was compared with the marketed capsule where, it was

found to librating the ORL much rapidly than the capsule. In the evaluation of taste

145 | P a g e

optimised formula was found to be palatable with no objectionable taste and odour.

Hence, the developed and optimised ORMTs are small attractive palatable dosage form

and can be happily chewed and sucked without water. But ultimately the clinical finding

in humans only can make it suitable for applying as generic dosage form and hence are

recommended.

Documents

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