INTRODUCTION:

Since long time the oral route has been considered the traditional route for delivering different type of formulations. It’s because of its simplicity of administration, patient acceptability and coast effectiveness production technique, the oral route ids regarded as most easy, practical and safe approach. Numerous oral drug delivery system has been created over the last few decades like the conventional oral control release system (COCRS) which serve as drug reservoir from which the active ingredients can be released over a specific time period and at control rate.

The gastrointestinal tract (GIT) presents additional difficulties for conventional drug delivery methods such as incomplete drug release, decreased dosage efficacy, and frequent dose requirements. Although conventional oral control release systems (COCRS) are the most commonly used for drug delivery, these systems also have some limitations such as low bioavailability caused by the gastrointestinal system, the pH of the gut flora, stomach residence time of the dosage form, and surface area.^1,2,3 The oral control release method has gained a lot of interest since it allows drugs to be released at predictable, controlled times. However, certain drugs have limited bioavailability due to inadequate absorption or GIT breakdown.⁴ Unpredictable stomach emptying time, gastrointestinal transit duration, and the existence of an absorption window in the upper small intestine for many days are a few more issues connected to this route.⁵ These all problems and the failure of conventional oral control release system to retain the drug into the stomach for longer period of time encouraged the researcher to develop such drug delivery system which can overcome these problems and to come up with drug delivery system which prolonged the gastric residence time and provide timely controlled release of a pharmaceutical dosage form which in turn will increase the total gastrointestinal transit time of the dosage form.⁶ In order to reduce the frequency of dosing, the researcher set out to develop a drug delivery system that would clinically offer effective plasma drug concentration over a prolonged length of time.1 In this discipline, the gastro-retentive drug delivery system (GRDDS) is the only novel technique.⁷ The controlled distribution of the medications is enhanced by the ability of these drug delivery systems to release the drug over an extended period of time at the appropriate rate and to the intended absorption location.^8,9 These drug delivery systems are suitable for the medication that have short biological half-life, low absorption in lower GIT, are unstable and weakly soluble at alkaline ph and exhibit local action at upper portion of the gut. Several manufacturing approaches have been used to design successful controlled release GRDDS such as raft forming system, floating system, mucoadhesive system, high-density system, magnetic system, expandable system. from all the methods mentioned above the name of the floating system itself suggests that it functions by remaining buoyant or afloat in the fluid of the gut, retaining desire and releasing drugs.

A prescription medicine called cinnarizine, also known as Diphenyl methyl (E)-1Piperazine -4-(3-phenylprop-2-enyl), has been approved for the treatment of motion sickness, nausea, and inner ear issues. It is also regarded as the first-line treatment for vertigo management.¹⁰ It was initially synthesized as antihistamine but now this is well established antivertigo drug.¹¹ It is a piperazine derivative, having molecular formula: C₂₆H₂₈N₂, molecular weight: 368.51g/mol, melting point: 118–122^∘C and biological half of 4-6 hours, it is white or almost white powder. It falls to BCS class II drug having a low solubility, it displays preference for gastric absorption. Cinnarizine is highly pH sensitive, with solubilities of 0.29mg/mL at pH 2, 0.017mg/mL at pH 5, and 0.002mg/mL at high pH of 6.5 (all findings were at 37°C), according to a study. It has a log P value of 5.71 and is an extremely lipophilic substance. Its repetitive dosing may cause accumulation of drug. Cinnarizine is a calcium channel blocker and an antihistamine from a pharmacodynamic perspective. It also exhibits anticholinergic, ant serotonergic, and antidopaminergic action. A mildly calming antihistaminic, cinnarizine works by inhibiting the H1 receptor. It is a specific inhibitor of calcium ion entrance. Its absorption primarily takes place in the proximal portion of the small intestine but it shows inadequate oral absorption thus having a low bioavailability when taken orally, which makes it a good choice for formulation as a floating dosage form. It remains ionized at stomach ph and unionized in intestinal ph because of lower pka value, so it displays less solubility in intestine.^12,13,14,15

This research project's main objective is to create a floating cinnarizine tablet that will stay in the stomach for a longer time, producing a more acidic environment that increases cinnarizine solubility and also increases the drug's absorption in the small intestine, improving the drug's bioavailability and also removing the need for a repetitive dosing schedule.

METHOD AND MATERIALS:

Materials:

Cinnarizine was provided as a gift sample by FDC Limited, Raigad, Maharashtra, India. HPMC K 100M, Sodium Bicarbonate, and Magnesium Stearate were purchased from Astron Chemicals. Ethyl Cellulose and Lactose were purchased from Chemdye Corporation.

Method:

Determination of UV absorbance maxima (λ max) of Cinnarizine^16,17

To determine the UV absorbance maxima of cinnarizine in a solution of 0.1 N hydrochloric acid (HCL) with a ph of 1.2, a sample of 20ug/ml strength was prepared. The sample was then analyzed using a double beam UV spectrophotometer manufactured by Thermoelectro Corporation. The analysis involved scanning the sample over a range of wavelengths from 200 to 400nm and comparing it gainst a blank solution of 0.1 N HCL

Fourier transform infrared (FTIR)¹⁸

FTIR analysis was performed on Cinnarizine (CNZ) using a Shimadzu Corporation instrument (QATR-S) with LabSolutions IR software. The QATR-S accessory used for the analysis had a diamond crystal with a contact area diameter of 1.8mm and was a type III monolithic diamond (wide band type). The ATR method was employed, and the incident angle was set at 45 degrees. The measurements' sensitivity was judged to be satisfactory, and the FTIR spectra were captured throughout a wavenumber range of 4000-400cm^-1. The sample used in the analysis was pure Cinnarizine powder, weighing up to 100mg.

Preparation of Gastro-retentive floating tablet¹⁹

The procedure for formulating a floating tablet involved the precise collection and weighing of the ingredients listed in Table 1.1. The components, except for magnesium stearate, were pre-blended in a pot for 10 minutes, followed by the addition of magnesium stearate and an additional 2-minute blend. The tablets were then manufactured using a manual rotary tablet compression machine (Shakti Pharmatech, model: SLP 1). A precise amount of the mixture was compressed using a mild compression force through a 6mm circular punch to produce tablets that could float.

Table 1.1: The ingredients in cinnarizine floating tablet formulation

Name of Ingredient	Optimization batches code of tablets and quantities of ingredients (mg)
Name of Ingredient	F1	F2	F3	F4	F5	F6	F7	F8	F9
Cinnarizine (mg)	50	50	50	50	50	50	50	50	50
HPMC K 100M (mg)	20	20	20	20	20	20	20	20	20
Ethyl cellulose (mg)	15	20	25	15	20	25	15	20	25
Sodium bicarbonate (mg)	20	20	20	24	24	24	28	28	28
Lactose (mg)	39	34	29	35	30	25	31	20	21
Magnesium stearate (mg)	6	6	6	6	6	6	6	6	6

Experimental Design²⁰

Nine complete factorial design points are included in a 3² level full-factorial design; nine tests were carried out overall, following the model. In this design, X1 and X2 are both dependent variables and independent or controlled variables. The concentrations of HPMC: EC and sodium bicarbonate (X2) were used as independent variables in the current investigation's experiment. The dependent variables were floating lag time (Y1) and drug release percentage (Y2). The optimization technique used in this study is based on a factorial design of experiment. This involves generating mathematical equations to represent the responses being investigated, in order to determine the best combination of inputs. A full factorial design with 3² experimental conditions was employed to further investigate the system, as detailed in Table 1.2

Table 1.2: For Floating Tablets of Cinnarizine, a full factorial design plan was used.

Formulation Code	Independent variables (X)
	Amount of EC (X1, mg)			Amount of Sodium Bicarbonate (X2, mg)
	Actual value	Coded value		Actual value		Coded value
F1	15	-1		20		-1
F2	20	0		20		-1
F3	25	+1		20		-1
F4	15	-1		24		0
F5	20	0		24		0
F6	25	+1		24		0
F7	15	-1		28		+1
F8	20	0		28		+1
F9	25	+1		28		+1
Y1= Floating lag time (FLT, secs)				Minimum
Y2=% Drug release				Maximum release up to 12hr
Specifying process parameters for optimisation based on test batches
Process variables			Statement		Comment
EC (X1)			15-20 mg		Varied
Sodium bicarbonate (X2)			20-28 mg		Varied
HPMC K 100M			20 mg		Fixed
Magnesium stearate			6 mg		Fixed
Lactose			35 mg		Fixed

*(-1) signifies a poor value, (0) demonstrates a middle value and (+1) demonstrate High value.

Assessment of floating tablets²¹

Among the pharmaceutical measures assessed in accordance with official compendia were tablet thickness, rigidity, friability test, medication quality, and content homogeneity.

Weight variation analysis²¹

The weight variation of a tablet can provide useful information regarding the variation in drug content. To determine the average weight of a tablet, 20 units or tablets were individually weighed using an analytical balance, specifically the Precisa XR 205SM-DR.

Table 1.3: Weight variation limit as per IP

Weight (mg)	% Deviation
Less than 80 mg	10
80-250	7.5
Above 250	5

Measurement of Thickness and Diameter²²

The amount of fill allowed to enter the die and the amount of pressure used during compression were what defined how thick a tablet would be. Three tablets were taken, and the Vernier caliper (Citizen, Japan) was used to measure each one's thickness and diameter. All tests were conducted in triplicate (n = 3).

Hardness determination²³

The hardness of three pills was assessed using a Hardness Tester (Monsanto type-Dolphine). Using a coiled spring, the amount of force needed to shatter a matrix tablet with opposite ends was measured. Each experiment was carried out three times (n=3).

Density²⁴

The density of the tablet was determined using the following formula after measurements of its weight, diameter, and height were taken.

Density (p) = M/V

The volume of the tablet (V)= πr²h

Where (ρ), M, and V are the density (g/cm³), Mass(g), Volume(cm³⁾, radius(cm), and height of the tablet respectively.

Studies on in vitro buoyancy²⁵

Conducting buoyancy tests in a 0.1N hydrochloric acid (HCl) solution with a pH of 1.2 required the use of the USP Apparatus 1 (Basket) technique (Electrolab, Mumbai TDT-08L). The mixture was swirled at 50 revolutions per minute and maintained at a temperature of 37.0-50.0°C. The floating lag time (FLT), also known as the floating time (FT), and the total floating time (FT), also known as the floating duration, were the two parameters that were to be measured.

Swelling Analysis²⁶

By observing a dose form's weight rise or water intake, swelling behavior was determined. The equation used to quantify water consumption expressed it in terms of percent weight increase.

Wu=(Wt-Wo)/Wo ×100

Wt. – Weight of dosage form at time t

Wo – Initial weight of dosage form

Quantitative analysis of Tablet²⁶

20 tablets from per batch were consumed. In a mortar and pestle, they were ground into powder. Each batch of tablet preparations underwent a separate assay in triplicate (n = 3). The following process was applied to each tablet.

Method:

A measured amount of powdered tablet containing 50mg cinnarizine was mixed with 50ml of 0.1N hydrochloric acid (HCl) solution. Whattmann filter paper No. 40 was used to filter the resultant solution, which was then diluted with 0.1N HCl to a volume of 100ml. After that, 1ml of the solution was diluted with 0.1N HCl and added to a 10ml volumetric flask. A UV-visible spectrophotometer was used to test the solution's absorbance.

In vitro dissolution analysis²⁶

For each batch, in-vitro dissolution tests were carried out (in triplicate) using the USP Apparatus 1 (Basket) technique (Electrolab, Mumbai TDT-08L) in 0.1 N HCL pH 1.2(900ml) as the dissolving medium, which was kept at 37 ±0.5°C at 50 rpm. Samples were occasionally removed throughout the dissolution experiment and replaced with an equivalent volume of brand-new dissolving medium. A 0.2-m membrane filter was used to filter the samples, which were then subjected to spectrophotometric analysis at a wavelength of 253nm and compared to a blank solution of 0.1N HCL with a pH of 1.2. To calculate the total amount of medication dissolved, a cumulative correction was used for the removed samples. Three times each (n=3) were used to conduct each experiment. At a temperature of 370.5°C and a basket speed of 50 rotations per minute, the dissolving test was conducted using a USP Type 1 apparatus with 900ml of 0.1N HCl, pH 1.2 dissolution media. At predetermined intervals of 0, 15, 30, 60, 180, 240, 300, 360, 480, 600, and 720minutes, 5 ml aliquots were sampled.

Scanning Electron Microscopy for surface morphology study²⁷

SEM (Nova NanoSEM 450) analysis of the surface morphology of the Cinnarazine tablet was performed. Before and after drying in the oven, cross sections of the tablet were collected, and their morphology was evaluated by SEM. With various magnifications, the SEM was captured at an acceleration and voltage of 5.00 kV.

Stability Study²⁸

This study was conducted to determine the stability of floating tablet F5 over a short period of time (1 month) in triplicate under two different storage conditions, such as ambient storage conditions (27:2°C; 65 15 RH), and 4012°C; 75+5% RH conditions, using a stability chamber (Model: JRIC-11, Osworld Scientific Equipments Pvt. Ltd, Mumbai, India).To examine each package's physical attributes, drug content, hardness, floating lag time (FLT), total floating time (TFT), and percentage of drug release, samples were taken at 0, 15, and 30 days.

RESULT AND DISCUSSION:

Determination of UV absorbance maxima (λ max):

The experiment involved analysing a sample of Cinnarizine at a concentration of 20µg/ml to determine its UV absorbance maxima in 0.1 N HCl with a pH of 1.2. This was done using a double-beam UV spectrophotometer manufactured by Thermoelectro corporation. The sample was scanned from 200nm to 400nm to determine the UV absorbance maxima, using a blank solution of 0.1N HCl with a pH of 1.2 as a reference. The maximum absorption wavelength (λ max) for cinnarizine was found to be 205nm.

Fourier transform infrared (FTIR):

FTIR was conducted using a Shimadzu Corporation instrument (model QATR-S) equipped with LabSolutions IR software. The FTIR spectra were obtained for Cinnarizine, HPMC K100M, Ethyl cellulose and mixture of Cinnarizine+HPMC K100+Ethyl cellulose. The spectra were recorded over a range of wavelengths from 4000 cm^-1 to 400 cm^-1.

The purpose of this experiment was to investigate the chemical composition and interactions of the drug and polymer components in the mixtures using FTIR spectroscopy. The FTIR spectra obtained for the pure drug and polymer samples were used as reference spectra to compare with the spectra of the mixtures.

As shown in Fig 1.1, the resulting spectra provide information about the functional groups present in the drug, polymer, and their mixtures, as well as any changes in the spectra resulting from the interactions between the drug and polymer. This information is useful for determining the chemical stability and compatibility of the drug and polymer, and for optimizing the formulation of drug delivery systems

Fig 1.1 Comparative FTIR spectra of (A) Cinnarizine; (B) HPMC K100M; (C) Ethyl cellulose; (D) Cinnarizine+HPMC K100+Ethyl cellulose

The cinnarizine FTIR was depicted in Fig 1.1 which states C-H stretching (aromatic, alkene) at 2957 cm^-1; C-H stretching (aliphatic, alkane) at 2936 cm^-1; C=C (aromatic stretch) at 1596 cm-1; CH2 (alkane at 1490 and 1447 cm^-1; C-N stretching at 1136 cm^-1 and =C-H (aromatic alkene) at 999 and 961 cm^-1. The same peaks had been observed in the FT-IR spectrum of physical mixtures, which clearly stated drug was compatible with all the excipients.

Physical evaluations study of Cinnarizine floating Tablet

Table 1.4 Results of In-vitro evaluation study of Cinnarizine floating tablets of Batches F1-F9

Formulation Number	Thickness (mm)	Diameter (mm)	Hardness (kg/ cm²)	Weight Variation (mg)	Quantitative analysis of Floating Tablet (%)
F1	4.0184±0.003	6.0556±0.0057	2.84± 0.11	149.96± 0.52	99.10± 0.04
F2	4.0184±0.003	6.0576±0.0071	3.04± 0.12	149.96± 0.52	100.03± 0.03
F3	4.0176±0.004	6.0552±0.005	3.03± 0.13	149.92± 0.56	99.76± 0.06
F4	4.0184±0.0037	6.0552±0.005	3.056± 0.14	150± 0.56	99.23± 0.02
F5	4.0184±0.0037	6.0556±0.0057	2.844± 0.12	149.92± 0.56	101.00± 0.04
F6	4.0176±0.0047	6.0576±0.0071	3.064± 0.15	150.04± 0.52	100.54± 0.03
F7	4.0184±0.0037	6.0556±0.0057	3.04± 0.10	149.88± 0.51	99.20± 0.06
F8	4.0184±0.0047	6.0576±0.0071	2.88± 0.16	149.92± 0.56	100.33± 0.33
F9	4.0184±0.0047	6.0576±0.0071	2.97± 0.15	149.92± 0.48	99.98± 0.04

In-vitro buoyancy studies:

The findings of the dissolution studies for all of the formulated floating tablets (FTs) indicated that they were able to float on the surface of the 0.1N hydrochloric acid (HCl) solution, demonstrating buoyancy. This floating behavior was due to the tablets' lower density compared to the density of the HCl solution. Specifically, the FTs' densities were such that they could remain afloat on the surface of the medium without sinking or disintegrating, as confirmed by their floating times exceeding 12 hours, as presented in Table 1.2. This prolonged floating behavior was most likely due to the presence of a gas-generating agent, such as sodium bicarbonate, in the FTs' formulation. The gas-generating agent generates carbon dioxide gas during the dissolution process, causing a decrease in the tablets' density and an increase in their buoyancy, leading to prolonged floating behavior.

Table 1.5 The in-vitro buoyancy study was conducted on Cinnarizine floating tablets of batches F1-F9 in 0.1N HCL with a pH of 1.2, and the results were obtained.

Batch code	FLT (sec)	FL (hour)	Effect on matrix
F1	74	>12	Swelling
F2	101	>12	Swelling
F3	78	>12	Swelling
F4	110	>12	Swelling
F5	84	>12	Swelling
F6	90	>12	Swelling
F7	86	>12	Swelling
F8	68	>12	Swelling
F9	62	>12	Swelling

Swelling study:

The molecular framework, hydrophilicity, and ionisation of the functional group all affect the degree of swelling of hydrogels, which represents the water content of the hydrogel at a state of equilibrium. A swelling study was carried out for 12 hours to look into the swelling behaviour of different formulations. The outcome of the swelling index of the optimized batch (F5) are presented in Table 1.3. The findings demonstrated that as the hydrophilic polymer progressively consumed water, the swelling's intensity grew with time. This hydrophilic polymer forms a gel-like barrier at the outermost surface, which then swells as it becomes hydrated. The dissolution and dispersion of the gelatinous layer occurs gradually, causing a repeated hydration swelling release process on newly exposed surfaces. This mechanism aids in maintaining the dose form's integrity. In summary, the swelling behavior of hydrogels is influenced by various factors, and the swelling process is a complex and dynamic phenomenon that involves the gradual absorption of water by the hydrophilic polymer, resulting in the formation of a gel-like barrier that promotes hydration swelling release.

Fig 1.2 Result of physical characteristics of sustain release Cinnarizine floating tablets axial and Radial swelling Index (mm) of optimized batch (F5)

In vitro dissolution study:

The percentage of sustained Cinnarizine release from the various batches (F1 to F9) over a period of 12 hours is shown in Fig. 1.3. According to the statistics, each batch of the drug displayed a prolonged release profile, with a percentage release that fell within a specific range.

Fig 1.3 The in-vitro dissolution study of Cinnarizine was obtained from floating tablets of batches F1-F9 in 0.1N HCl with a pH of 1.2. The results are presented as mean ± standard deviation (n=3).

Scanning Electron Microscopy (SEM) Analysis:

The use of Scanning Electron Microscopy (SEM) techniques was employed as a means of investigating the morphological features of the tablets, with a particular emphasis on verifying the formation of pores and cracks as observed in the photograph depicted in Fig 1.4. After 8 hours of dissolving, it was discovered that pores were beginning to form. This suggests that the medication was released by the process of diffusion through these pores. These findings provide substantial evidence to support the hypothesis that the observed mechanism of drug release is due to the formation of pores within the tablet structure. By utilizing SEM techniques, a comprehensive understanding of the physical properties of the tablet structure was achieved, which could ultimately assist during the creation of more efficient drug delivery systems.

Fig 1.4 Photographic image of SEM study Before swelling (A-D) and After 6hrs swelling (E-H) at 250, 500, 1000, 5000XM.

Experimental Design:

In this study, a total of 9 formulations were developed using a 3² factorial design. The formulations were made by varying the ratio of HPMC:EC (X1) and sodium bicarbonate (X2) upon 3 various concentrations (low, medium, and high). The optimization response parameters investigated were FLT (Y1) and the percentage of drug release up to 12 hours (Y2).

Fitting of data to Model:

The results of the optimization response parameters (Y1 and Y2) for all formulation batches are presented in Table 1.4. These responses were fitted to different mathematical models using Design Expert State-Ease' 11.1.2.0. The best-fitted models were observed to be either quadratic or linear Table 1.6 lists the values of R², revised R², and anticipated R² for different models. The ANOVA results showed that among the prepared batches during optimisation, a linear model has been recommended to Y1 as well as a quadratic model had been recommended to Y2.

CONCLUSION:

The current study's objective was to create a sustained drug delivery system for Cinnarizine using floating tablets with sodium bicarbonate and ethyl cellulose as excipient. It was found that the amount of sodium bicarbonate and ethyl cellulose significantly affected the hardness and floating behavior, and drug release of the tablets. A minimum of 20mg of ethyl cellulose and 24mg of sodium bicarbonate were necessary for floating tablet for 12hr. In addition, the incorporation of Ethyl cellulose and HPMC K 100 M in the matrix layer further improved the floating behavior and sustained drug release of tablets. The optimized formulation had a floating period of more than 12 hours and, at the end of 12 hours, had a cumulative release of drug 98.82%. Since they reduce the need for repeated dosing and increase Cinnarizine bioavailability, the newly developed Cinnarizine floating tablets represent a promising substitute for traditional dosage forms.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank FDC Limited, Raigad, Maharashtra for their kind support for providing drug sample.

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Received on 12.05.2023 Modified on 11.09.2023

Asian J. Pharm. Res. 2024; 14(1):1-9.

DOI: 10.52711/2231-5691.2024.00001

Responses	Model	Sequential p-value	Adjusted R²	Predicted R²	Remarks
Y1 (Floating Lag time, secs)	Linear	< 0.0001	0.9680	0.9373	Suggested
	2F1	0.1586	0.9752	0.9344
	Quadratic	0.6851	0.9678	0.8555
	Cubic	0.2100	0.9957	0.9031	Aliased
Y2 % Drug release	Linear	0.0107	0.7058	0.4968	Suggested
	2F1	0.6655	0.6612	0.0930
	Quadratic	0.7472	0.5351	-0.7936
	Cubic	0.6329	0.4413	-11.7279	Aliased

Responses (Y)	Source	Sum of square	df	Mean Square	F-value	p-value	Remark
Y1= Floating Lag time (secs)	Model	1834.83	2	917.42	121.87	< 0.0001	Significant
	Amount of EC	1568.17	1	1568.17	208.32	< 0.0001
	Amount of sodium bicarbonate	266.67	1	266.67	35.42	0.0010
	Residual	45.17	6	7.53
	Cor total	1880.00	8
Y2= % Drug release	Model	32.50	2	16.25	10.60	0.0107	Significant
	Amount of EC	28.25	1	28.25	18.42	0.0051
	Amount of sodium bicarbonate	4.25	1	4.25	2.77	0.1470
	Residual	9.20	6	1.53
	Cor total	41.71	8

Sr. no.	Responses	Equation for Actual Factors	Equation for coded factors
1	Floating Lag time (Y1, secs)	+59.00000 + 3.23333 A - 1.66667 B	+83.67 + 16.17 * A - 6.67 * B
2	Drug Release (Y2, %)	+111.50556 - 0.434000 * A - 0.210417 * B	+97.78 - 2.17 * A - 0.8417 * B

Optimized batch	Zero-order model	First-order model	Higuchi model	Hixson Crowell model	Korsmeyer-Peppas Model	Best Fitted Model
R²	0.9919	0.675	0.9432	0.8886	0.9623	Zero order Model

Storage condition	Formulation Stored without packaging
	Floating lag time		% drug release
	Initial	After one month	Initial	After one month
34°C/11%RH (Ambient temp)	82.34	82.34	98.82	98.82
40±2°C/75±5% RH (Stability chamber)	83.24	82.34	99.76	99.76
Formulation Stored in Bristle strip
34°C/11%RH (Ambient temp)	82.34	82.34	98.82	98.82
40±2°C/75±5% RH (Stability chamber)	83.24	83.24	99.76	99.76