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 International Journal of Medical Sciences and Pharma Research 

Open Access to Medical Science and Pharma Research

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Preparation and Evaluation for Pulstile Release Capsules of Phenytoin

Kalidas Mandal¹*, Dr Rakesh Kumar Jat ²

¹ Research Scholar, Institute of Pharmacy, S.J.J.T. University, Chudela, Jhunjhunu, Rajisthan, India 

² Professor & Principal, Institute of Pharmacy, S.J.J.T. University, Chudela, Jhunjhunu, Rajisthan, India 

 

 

Oral The core tablets were covered using an IdealCures Pvt. Ltd.'s Deluxe Model Pharma R and D Coater.Ltd., Mumbai, India) with polymer blend of ethyl cellulose (EC 10 cps) with HPMC E15/60 dissimilar ratios of 60 Eudragit L100 (80:20, 70:30, andand 60:40). In order to dissolve eudragit L 100, 3 percent v/v water was added to the solvent mixture of isopropyl alcohol and dichloromethane (70: 30), which was used to  make the coating solution. The outside layer was amended with 60 Talcum (twenty percent weight by weight, depend upon the full amount masses of polymers solution for preventing staining. Dibutyl phthalate, or  DBP, was used as a plasticizer at a 20 percent weight-tto- weight ratio. Up to weight growth of 8, 10, and 12 percent w/w, tablets were coated¹.

The following process variables were used for the coating: inlet temperature of 40–45 °C, pan rotation speed of 35–40 rpm, peristaltic pump speed of 1–2 rpm, and 1 bar of  atomization pressure. Tablets were then further dried for a further 30 minutes at 40 °C in a coated pan to eliminate any remaining sol².

2. MATERIALS AND METHODS

2.1 Materials

Experimental Design

A comeback surface design called the central composite design (CCD) gives information on straight impacts, interaction effects, and curvilinear effects and has widely been used for formulation optimization in dosage forms. It requires A necessary smallest amount number of experiments is   are requisite to generate a mathematical tendency in the experimental intend area and recognize the perfect amount of experimental factors required for a given response (Singh , 2012). The central composite design is  composed of 3D designs known as factorial designs with centered points coordinated with a group of start points that allow estimation of curvature. In  produced time-controlled release tablet, % of HPMC E15 in coating composition; X2 studies were conducted at three distinct levels (-1, 0, and +1)³.

Formulation of modified pulsincap pulsated drug delivery system 

Beads that were equal to Lamotriazine sulphate and theophyline were accurately weighed and filled into the head filling.

Pulsincap coating

The method followed was dip caoating at 5% w/w capsules prepared using the solvent combination of acetone:ethanol (8:2) and dibutyl phthalate (0.75%). At the next step, these capsules are completely dipped in the 5% CAP solvent solution mixture and dried carefully. This process is carried on until the required mass of 8 to 13% is obtained, plus the capsule has the capacity to endure worsening in 0.1 N Hcl for predetermined time duration of two hours.Pulsincap assessment with modifications cellulose pthalate thickness⁴.

Evaluation of modified pulsincap

Thickness of cellulose pthalate coating

In this method, the ultimate thickness of the solvent-entrapped CAP-coated capsule was calculated separately with a vernier calliper and reported⁵.

Weight variation

In this method, 10 to 12 capsules were randomly selected from each particular batch and weighed and calculated separately to check the weight variation.

Interaction between drug polymers

In this method, the major reaction within polymer and medicament is found quantitatively. Initially, FTIR spectra were taken of the physical mixture of were done by applying the KBr pellet technique. Collectively, the sample mixtures were scanned. The KBr abundance with the specified rotation of 1% was measured with FTIR spectra.In-vitro dissolution studies were carried out using dissolution apparatus by employing the USPXII dissolution test apparatus by the basket method. Then the coated pulsincap capsules are taken and placed in the baskets such that the capsules are completely immersed in dissolution media and seem not to be floating⁶.

By the sequential pH change method, three different dissolution media like PH 1.2 and PH 6.8 were used in order to rein act and duplicate the GI tract's PH alterations.

Initialy, for the first 2 hours, PH 1.2 was used to maintain gastric emptying and flush the GI tract. Later, it was removed and replaced with frasile saline phosphate buffer, PH. After 3 hours, which corresponds to the typical intestinal passage duration of 3hours, the pills was distorted to fresh PH 6.8 media (1.2, 6.8, and 7.4) at later hours.Usually, At any given moment, 900 cc of the dissolving medium were worn As the temperature augmented, the control of 100 rpm revolving was regularly maintained atdegrees Celsius.Around  At usual intervals, 88 5 ml of the disbanding media was steadily detached from each tie and replaced with new dissolution medium. the detached samples at that point a particular time interval were analysed at 237 nm with UV absorption spectroscopy⁷.

Pulsaile capsule invitro release

The USPXXIII was used in 47 dissolution investigations for the in vitro release of the pulsatile capsule.

Disoluton paddle method apparatus. Initially, the capsules are taken and tightly was threaded onto the paddle made up of cotton such the pill is completely submerged in the dissolving at medium and seen such that it is not completely immersed but should be floated. By following the sequential ph change method, to simulate and monitor the pH variations throughout the GI tract, including PH 1.2, 7.4, and 6.8 disolution mediums were used and utilised. Initially, pH 1.2 was used and maintained for 2 hours, minimising the GI tract, and later, a fresh phosphate buffer of 7.4 ph was added to it. A colonic or intestinal fluid with a pH of 6.8 phosphate buffer was further when the average was 3 hours old.taken out. Then simultaneously, the dissolution medium is replaced with fresh medium at a time interval when the dissolution medium is withdrawn and a rotation speed of 100 rpm plus or minus 37 degrees Celsius is maintained. 900 millilitres At every interval, of the dissolving average were used. Next, the samples that were withdrawn UV absorption spectroscopy was used to analyze 12 at 210 nm and decide the increasing percentage discharge.. Then simultaneously, the dissolution medium is replaced with fresh medium at a time interval when the dissolution medium is withdrawn and a rotation speed of 100 rpm plus or minus 37 degrees Celsius is maintained⁷.

Pulsinacap stability studies 

 Studies on constancy were conducted to appraise the constancy with respect to its characteristics, including its physical, chemical, medicinal, and toxicological properties. The main interaction is to carry out stability testing to determine the quality of the drug, which is the formulation with its excipient and other components that have gradations with the collision of outside rudiments like temperature, humidity, and light that prove good or instable at the prescribed storage conditions, shelf lives, and retest periods according to ICH guidelines⁸.

ICH explains the storage condition. 

• Long-term testing
• Accelerated testing       

Preparation of osmotically controlled pulsatile release capsules

The capsule device's assembled state (capsule size 2). Push, active, and plug layers are added in layers from bottom to top in a capsule. Separately produced in tablet form, the push, active, and plug layers were then placed within the capsule. An opening was formed in the cap toward the plug side after a semi porous membrane was functional to these preparation units⁹.

formulation of push, active along with plugtablets. All tablets were prepared by direct compression, with all other ingredients, followed by sieve no. 20 to remove any other big lumps. The medicine was diverse for 10 minutes to produce the mixtures for the active medicine. Step by step, for 60 seconds each, pure talcum powder along with Mg salt of stearic acid had been mixed into until that time mentioned mixture. The resultant mixture had been pressed to a fifty milligram tableting utiling similarly, blends for push and plug tablets were prepared by mixing all ingredients in the same order as active tablets. The blend was compressed into tablets of different weight using a5 mm diameter flat faced punch. 60 This total mixer had been prepared to compression had been carried out to determine Car’s index, Hausnner’s ratio along repose angle to confirm flow properties as discussed in the previous chapter. creation of capsules with osmotically regulated pulsatile releases Microcrystalline cellulose, Eudragit L 100, Perampanel, polyethylene oxide, and ethylcellulose were gifts from the listed sources. Methanol and acetonitrile are both HPLC-grade substances. All compounds utilized, including the medication PhenytoinThe grade for 177 was analytical. medication delivery system with pulses¹⁰

Development A total lag time of about 4 hours was intended to be provided by the pulsatile capsule. The recommended quantity form incorporated a hydrocolloid bung that preserved an inexplicable capsule body containing drug-loaded pellets inside, and a soluble capsule cap.capsule cap as its basic structure. For the duration of two hours, a hydrocolloid stopper was implanted to prevent pellet release. To give an extra 2 hours of lag time and reduce the variability in stomach transit time, was further coated onto the plugged capsule. Finally, employing The external enteric layer of the preserved hydrocolloid plug andcapsules, hours was achieved. At pH 6.8, it was anticipated that the enteric coating would disintegrate. Water was used as the granulating liquid and a 2 percent w/v PVP K30 binder to create the pellets through extrusion and spheronization. Formalin fumes were on the rampage into the air after a response flanked by empty gelatin capsule bodies and a 15 percent v/v solution of formalin.formaldehyde solution and potassium permanganate  to produce bodies of insoluble gelatin capsules. The aforesaid treatment was not applied to the capsule caps, leaving them water-soluble¹¹.

Table 1: - Formulation for pulsatile release capsules of Phenytoin

 

Preparation of pellets

Procedure: Step I: Extrusion spheronisation pelletisation method is utilized for preparation and formulation of pellets of medicaments phenytoin

Step II: All ingredients along with Perampanel and theophyllin had been grinded like aerosil, crosscarmillose sod and lactose. Then all had been screened within Sieving Number. fourty, pelletisation proceded.

Step III: With mixer of planetary type, aforementioned medicaments along with additive powder had been mixed thoroughly for twenty minutes.

Step IV: For preparing mass of dough, which a piston extruder was then used to extrude, Binder of P.V.P.K 32 iso propyl solution was utilized then gradually mixed with aforementioned mixture upto 28 mins (1 millimeter aperature).

In to 4^th step, extrudates of theophylline had been spheronised upto 11 mins at 749 revolution per minutes (speed of oxygen: one kilogram per centimeter squar).

Step V: these pellets had been dried with fludized bed dryer for drying¹². 

Determination of particle size and external morphology

The pellets were placed inside clean brass specimen studs, coated with wet solvent paint, allowed to dry, and then photographs were taken. The optical microscope was used to determine the particle size of the pellets, and their external morphology was determined using a scanning electron microscope (SEM)¹³.

Determination of drug content

Phenytoin pellets weighing 1 g were thoroughly crushed then dissolved in 100 ml of pH 7.4 phosphate buffer over the course of 24 hours in an orbital shaker incubator. The filtrate was then appropriately diluted with pH 7.4 before being subjected to spectrophotometric analysis at 272 and 289 nm. Utilizing the medicine's standard calibration curve, the amount of drug content was calculated in triplicate¹⁴.

Uniformity of weight (Weight variation test)

Phenytoin pellets weighing approximately 450 mg each were taken for the weight variation test in accordance with USP-30-NF25, 2007, 103 and the connote weight's average deviation was computed¹⁴.

Friability test

According to USP-30-NF25, 2007, theophylline and Perampanel pellets of known mass (450 mg) were put in a Roche Friability tester and put through impact testing at 50 rpm for five minutes. The pellets were then put through a sieve with a no. 16 opening (1000 m), the weight of the pellets that remained on the sieve was recorded, and the equation below was used to determine how friable the pellets were¹⁵: 

Friability (%) = [1- initial weight / weight retained after 100 rotations] × 100.

Disintegration test

One pellet weighing around 1 g was inserted in each tube of the Cintex disintegration apparatus's disintegration basket, which was then covered with circular plastic discs. Water was used as the medium, which was kept at a temperature of 37 °Cwith 30 cycles per minute of operation. The duration of the pellets' disintegration was recorded and repeated in three different ways¹⁶.

In-vitro dissolution test of pellets

Phenytoin pellets' in vitro dissolution profiles were established in accordance with USP-30-NF25, 2007, using the paddle method and the USP XXIII dissolution test apparatus (900 ml of pH 1.2, 6.8, and 7.4-phosphate buffer, 100 rpm at 37 0.50 C). Pellets containing 400 mg each of theophylline and Perampanel were added to the dissolving apparatus basket. At appropriate intervals, 5 ml of the sample were taken out of the dissolving medium and replaced with new buffer in the same volume. With the use of UV-visible light at a wavelength of 272 nm, the filtrate's absorbance was calculated¹⁷.

RESULT AND DISCUSSION

Pulsatile release capsule was formulated and examined as the method of preparation and precompression with post compression tests have been applied to the prepared products/ the in vitro dissolution, disintegration tests, friability, drug content uniformity, weigth variation, test are used for the formulation. The additives are polyethylene glycol 400, sodium chloride, purified talc, magnesium stearate, micro crystalline cellulose and starch are added and formulation have been developed according to procedure mentioned above. The product was find according to pharmacopoeial requirement.

The compatibility studies, precompression characteristics and post compression characteristics and other quality control tests like weight of variation, content uniformity, disintegration test, dissolution rate, wetting time, saliva disintegration time, thickness, tensile strength, water absorption ratio, invitro release study.

The standard curve of each medicament is made with the spectrophotometer. The medicament is scanned for wavelength maxima where maximum absorption takes place. The diluted solutions are prepared according Beer and Lambert law. The absorption was noted in microgram concentration of medicament in the limit of 1 to 100 microgram per milliliter. The graph was plotted between concentration and observed absorbance. There is straight line passing through the origin and follow Beer Lamber Law of dilute solutions for absorption.

Summary and Conclusion

The dissolving film in mouth had been prepared and formulated that are immediate release formulations of phenytoin. Phenytoin is most popular prototype medicament for grand mall epilepsy. Lamotrizine is broad spectrum antiepileptic medicament that is widely utilized in the treatment of all types of epilepsies like grand mal, petimal, status epilepsy, myoclonic, atonic epilepsies. The film contains micro crystalline cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidine plastic polymers and evaluated for their tensile strength, water absorption ratio, invitro delivery pattern, thickness, saliva dissolution test, folding endurance. The film contain flow promoter magnesium stearate and sweetener mannitol, sucrose, aspartame, sodium saccharin and flavouring agent, colouring agent with other exicipients.

the PVK polymers and Udragit RL are other polymers utilized for film coating tablets, talcum powder is utilized as flow promoter to the formulations and these are ingredients are mixed properly and compressed directly to the tableting machine. The excipients should be directly compressible and compatible with the preparations and formulations. The stability studies had been perfomed at accelarted temperatures, acidic environment, basic environment, pH and hydrolysis. The humidity and temperature should be taken properly.

Conflict of Interest: Author declares no potential conflict of interest with respect to the contents, authorship, and/or publication of this article.

Source of Support: Nil

Funding: The authors declared that this study has received no financial support.

Informed Consent Statement: Not applicable. 

Data Availability Statement: The data supporting in this paper are available on the request from corresponding author. 

Ethics approval: Not applicable.

REFERENCES

1. Chien Yie W Novel drug delivery systems. 2nd ed. Marcel Dekker.Drugs and pharm Sci. 2021; 50: 139-140.

2. Swamivelmanickam M, Manavalan R, Valliappan K. Mouth Dissolving Tablets: An Overview. Int. J. of Pharm. Sci. and Res. 2020; 1(12): 43-55.

3. Jain CP, Naruk PS. Formulation and evaluation of fast dissolving tablets of valsartan. Int J. of Pharm. & pharm Sci. 2019; 1(1): 219-226.

4. Jeevan JB, Suneela G. Development of Fast Dissolving Tablets of Glibenclamide Using Crospovidone and its Kneading Mixture. Ind J. of Pharm Edu. Res. 2020; 44(4): 334-340.

5. Anjan KM, Murthy PN, Jagannath S, Sudarsan B, Sahoo SK. Formulation Design and Optimization of Mouth Dissolving Tablets of Levocetrizine Hydrochloride Using Sublimation Technique. Ind J. of Pharm.Edu.Res. 2019; 43(1): 39-45.

6. Seager H. Drug-delivery Products and the Zydis Fast-dissolving Dosage Form. J. Pharm. Pharmacol. 1997; 50: 375-382. https://doi.org/10.1111/j.2042-7158.1998.tb06876.x PMid:9625481

7. Kumar GA, Wadood SA, Maurya SD, Ramchand D, Interpenetrating polymeric network hydrogel for stomach-specific drug delivery of clarithromycin: Preparation and evaluation, Asian Journal of Pharmaceutics-October-December 2010; 179-184. https://doi.org/10.4103/0973-8398.76738

8. Bradoo R. Fast Dissolving Drug Delivery Systems, JAMA India. 2001; 4(10): 27-31.

9. Kuchekar BS, Atul, Badhan, C. Mahajan HS. Mouth dissolving tablets: A novel drug delivery system. Pharm Tim. 2003; 35: 7-9.

10. Behnke K, Sogaard J, Martin S, Bauml J, Ravindran AV, Agren H, et al. Mirtazapine orally disintegrating tablet versus sertraline: A prospective onset of action study. J Cli Psy pharmacol. 2003; 23: 358-64. https://doi.org/10.1097/01.jcp.0000085408.08426.05 PMid:12920411

11. Fu Y, Yang S, Jeong SH, Kimura S, Park K. Orally fast disintegrating tablets: Developments, technologies, taste-masking and clinical studies. Cri Rev The Dru Car Sys. 2004; 21: 433-76. https://doi.org/10.1615/CritRevTherDrugCarrierSyst.v21.i6.10 PMid:15658933

12. Dollo G, Chevanne F, Le CP, Chemtob C, Le VR. Bioavailability of phloroglucinol in man. J Pharm Bel. 1999; 54: 75-82.

13. Maurya SD, Prajapati S, Gupta A, Saxena G, Dhakar RC, Formulation Development and Evaluation of Ethosome of Stavudine, Indian J.Pharm. Educ. Res. 2010;44(1)

14. Maurya SD, Aggarwal S, Tilak VK, Dhakar RC, Singh A, Maurya G, Enhanced Transdermal Delivery of Indinavir Sulfate via Transfersomes, Pharmacie Globale (IJCP) 2010;1(06):1-7

15. Allen LV, Wang B. Process for making a particulate support matrix for making a rapidly dissolving dosage form. US Patent.2001; 6,207,199.

16. Allen LV, Wang B. Process for making a particulate support matrix for making a rapidly dissolving tablet. US Patent. 1996; 5,587,180.

17. Fitri K, Khairani TN, Sianturi KT, Leny L, Hafiz I, Anti-inflammatory Activity of Ethanol Extract of Lotus (Nelumbo nucifera G.) Seed Against White Male Rats Using Paw Edema Method, Journal of Drug Delivery and Therapeutics,2021;11(4):1-4 https://doi.org/10.22270/jddt.v11i2-S.4622

18. Bhaskaran S, Narmada GV. Rapid dissolving tablet A Novel dosage form Ind Pharm. 2002; 1: 9-12.

19. Koizumi K, Watanabe Y, Morita K, Utoguchi N, Matsumoto M. New method of preparing high-porosity rapidly saliva soluble compressed tablets using mannitol with camphor: A subliming material. Int J Pharm 1997; 152: 127-31. https://doi.org/10.1016/S0378-5173(97)04924-7

20. Meyers GL, Battist GE, Fuisz RC. Process and apparatus for making rapidly dissolving dosage units and product there form. PCT Patent WC 95/34293-A1; 1995.