INTRODUCTION:

Pharmaceutical Excipients:

An excipient is an innovative substance which is used to convert drug molecule into dosage form which is suitable for patient administration. Excipients are the major part of pharmaceutical dosage form as it is included for various purposes such as stabilization of dosage form for long period of time, for improving physical properties of active ingredient or for increasing the bulk of dosage form containing potent drug¹.

Excipients plays a vital role in the performance and quality of drug delivery system. Excipients maybe used for Enhancing thestability of dosage form i.e. drugs which are light sensitive or sensitive to some environmental conditions (antioxidant and UV absorber)

Excipients which are used to modify drug release (disintegrants) For controlling the drug release from dosage form (polymers) For improving bioavailability (solubilizers) Excipients necessary for manufacturing technology (binders, glidants, fillers) Ideal properties of pharmaceutical excipients It should be pharmacologically inactive and compatible with active ingredient. It should be sterile and should not alter the pharmacological action of active ingredient. It should have physical and chemical stability. Be available at relatively lower cost with better quality.

Pharmaceutical Excipients are categorised into four different classes

1. Single entity excipient

2. Physical mixture of different excipients

3. New chemical entity

4. Coprocessed excipients

No one single entity excipient alwaysfulfill all required performance and requirements for manufacturing active ingredient into a specific dosage form so there is need to use combination of two or more different excipients together for better and multiple functionality purpose.

Coprocessed Excipient:

Coprocessed excipient involves physical processing of two or more excipients mixture without any chemical changes to obtain multiple functionality, to minimize, to synergize desired properties and to mask or overcome undesired properties of existing excipients.

Coprocessed excipients shows added functionality of excipients and provide excipient with improved properties than using physical mixture of excipients or single entity excipient. No one existing single component excipient would able to meet all requisite functions for formulating specific dosage form and synthesis of new excipient entity requires long period of time and also it is costly. So it is beneficial to use existing natural excipients in mixture with some physical modification with respect to cost, functionality and safety concern. Excipients obtained from natural sources such as plant are safe for use in dosage form than chemically synthesised compounds.

In past 1986, Mehra et. al. Patented microcrystalline cellulose and calcium carbonate coprocessed excipient used for vitamin tablets by direct compression method². Coprocessed excipient for chewable tablet was prepared by Ratnaraj and Reilly in 1997 from guar gumand microcrystalline cellulose³.

Coprocessed excipients have some advantages^4,5,6

Ease of production due to minimization of number of excipients by combining all functionality in one excipient

Coprocessed excipient minimises the steps involved in production and also minimises errors.

It is cost effective than synthesis of new chemical entity.

Incase of tablet formulation compressibility is the important parameter this property can be obtained by using coprocessed excipient.

Coprocessed excipients form newly exposed surface upon compression and break the lubricant coherent network and therefore it shows less lubricant sensitivity.

Fast disintegration property also obtained from coprocessed excipient by different mechanisms such as swelling.

Improved flow of final powder blend is obtained by physical modification and by controlling particle size distribution of excipient mixture.

Coprocessing do not involve any chemical modifications.

Coprocessing involves following general steps^7,8:

a. Group identification of excipients: Plasticity and brittleness should be in balance to obtain good excipient, so it requires you identify group of excipient first to optimize concentration of plastic and brittle material. Generally all coprocessed excipients contain brittle material in large amount. Plastic and brittle material combination reduces the capping and lamination defect in tablet

b. Particle size assessment: It mainly affects the flowability of end product. Particles are converted to uniform size to obtain good flow characteristics.

c. Technique selection for coprocessing: Depending upon material characteristics and physical properties suitable technique is selected.

d. Process optimization: For good functionality excipient process parameters for preparation and excipients composition are optimized.

Different techniques used to produce coprocessed excipients such as solvent evaporation, spray drying, roller compaction, wet granulation etc.

a. Roller compaction: It is similar to dry granulation technique. Powder blend is compacted by placing material between rollers and then granulated. It is used for moisture and temperature sensitive materials.

b. Wet granulation: By using liquid dump mass of material to be processed is converted into dump mass and then it is granulated and dried. Fluidized bed dryer is mostly used for this technique.

c. Hot melt extrusion: Without solvent, material is heated to melt and then cooled to get aggregate, which is then passed through sieve.

d. Spray drying: This technique produce material with more spherical shape with good flow properties. It involves drying of solution or suspension of material in hot medium.

e. Roller drying: It provide final coprocessed excipient in crystalline form.

f. Co-transformation: This method utilizes heat or solvent to swell and open one excipient and after opening another excipient is incorporated into first excipient.

g. Melt granulation: Binder which is meltable in its crystallineform is used and mixture of excipients with that binder is heated to melt the binder and after cooling, granulated.

h. Solvent evaporation: This method involves dissolution of coating excipient in volatile solvent and then other excipient being coated added to that solution and evaporation of solvent.

i. Milling: Any milling machine is used.

Table: Some coprocessed excipients with improved functionality

Drug used	Excipient mixture used	Technique used for co-processing	Outcome of study	Ref
Terbutalin sulphate	Ocimum bascilium mucilage, Mannitol	Solvent evaporation	With the coprocessed excipient of Ocimum bascilium mucilage and Mannitol Terbutalin sulphate mouth dissolving tablet is prepared with disintegration time of 8 sec. Quick disintegration is assisted by the presence of Ocimum bascilium mucilage which has excellent disintegration property.	9
Finasteride	Crospovidone, sodium starch glycollate, Aerosil, Crospovidone, microcrystalline cellulose PH102, croscarmellose sodium, colloidal silicon dioxide.	Solvent evaporation	Flow properties of orodispersible tablets of Finasteride is improved by using coprocessed excipient. Crospovidone and microcrystalline cellulose is responsible for good flow and Mannitol and aerosil provide good orodispersiblity.	10
Vitamin C	Polyethylene glycol 6000 and Mannitol.	Wet granulation	Coprocessed excipient prepared from Mannitol-PEG6000 results in improved compactability.	11
Metoclopramide hydrochloride	Crospovidone and croscarmellose sodium.	Solvent evaporation	Dissolution rate of fast dissolving tablets of metoclopramide is improved by preparing coprocessed excipient which reduce the disintegration time and also provide the good flow property.	12
Chlorpheniramine maleate	Microcrystalline cellulose PH101 and kollidon k30.	Spray drying	Directly compressible tablet of Chlorpheniramine maleate with no capping and laminating defect are prepared by improving compressibility and of drug using microcrystalline cellulose and kollidon k30 coprocessed excipient.	13
Metoclopramide hydrochloride	Crospovidone, kyron T-314.	Solvent evaporation	Dissolution and drug release are improved by coprocessed excipient of crospovidone and kyron T – 314.	14
Salbutamol sulphate	Crospovidone, Mannitol, sodium saccharine and talc.	Solvent evaporation	By using coprocessed excipient of crospovidone, Mannitol, talc and sodium saccharine disintegration time is reduced and drug release is improved.	15
Repaglinide	Microcrystalline cellulose, Mannitol and aerosil.	Spray drying	Coprocessed excipient prepared from microcrystalline cellulose, Mannitol and aerosil improves the flowability, compressibility and drug dissolution.	16
Cefuroxime axetil	Mannitol, microcrystalline cellulose and Kyron T – 314.	Spray drying	Coprocessed excipient prepared has greater dilution potential and disintegration time of about 13 sec.	17
Repaglinide	Microcrystalline cellulose, Mannitol and banana powder	Spray drying	Fast dissolving tablet of Repaglinide shows wetting time of 30.33 sec.	18
Ezetimibe	Cross-linked polyvinylpyrolidone and calcium silicate.	Milling, Spray drying or freeze drying.	Dissolution and extent of drug release of Ezetimibe tablet is improved by using coprocessed excipient. Milling process shows more better improvement in dissolution than spray drying method.	19
Glibenclamide	Mannitol and microcrystalline cellulose.	Spray drying	Glibenclamide tablet shows dispersion time of 22.23 sec. Presence of Coprocessed excipient of MCC and Mannitol improves flowability and compressibility.	20
Glimepiride	Polyvinylpyrrolidone, maltodextrin and polyethylene glycol.	Spray drying	Dissolution rate of glimepiride solid dispersion is increased by using coprocessed excipient.	21
Amoldipine besylate, Methyldopa.	Crystalline Mannitol and alpha chitin.	Dry granulation, wet granulation and spray drying.	Coprocessed excipient prepared from mannitol and chitin shows superdisintegration property with good chemical stability and binding property.	22
Propranolol HCL	Xanthan gum and methyl cellulose.	Microwave drying	Coprocessing of xanthan gum and methyl cellulose provide better flowability and compressibility and show Higuichi model release of drug.	23
Paracetamol	Microcrystalline cellulose and alpha lactose monohydrate.	Microwave drying	Obtained modified excipient show good flowability with low segregation property and improve tabletability and compressibility.	24
Acceclophenac	Dibasic calcium phosphate anhydrous, polyethylene glycol 4000, Crospovidone	Melt granulation	Coprocessed excipient prepared by melt granulation process is cost effective and produces good flow properties.	25
Vitamin C	Microcrystalline cellulose and calcium phosphate	Solvent evaporation	In the present coprocessed excipient microcrystalline cellulose acts as a disintegrant and calcium phosphate is responsible for providing improved compactability.	26
Venlafaxine HCL	Xanthan gum and guar gum	Solvent–Antisolvent method	Xanthan gum and guar gum coprocessed excipient shows enhanced disintegration time and also provide the good gelling and binding property.	27
Diclofenac, Iron polymaltose, Amoxicillin.	Microcrystalline cellulose, colloidal colloidalsilicon dioxide and crospovidone.	Spray drying	Prepared coprocessed excipient is tested for their functionality by preparing Amoxicillin tablets, by using this coprocessed excipient dispersible tablet is prepared which show better suspensability. Diclofenac tablet with better binding capacity and iron polymaltose tablet with better fragility are obtained using coprocessed excipient.	28
Paracetamol	Polyvinylpyrrolidone, pulverulent carrier containing lactose.	wet granulation and spray drying.	Tablet prepared by using coprocessed excipient of polyvinylpyrrolidone and pulverulent carrier are having greater hardness with minimum abrasive property.	29
Metoprolol succinate, Theophylline.	Polyoxyethylene oxide and hydroxyl propyl methyl cellulose.	Roller compaction	Sustained release matrix polymer is formed by using Polyoxyethylene and HPMC which release the drug slowly.	30
Aspirin	Microcrystalline cellulose and gallactomannan	Spray drying	Coprocessed excipient obtained from combination of microcrystalline cellulose and gallactomannan produce good mouthfeel, mask unpleasant odour and taste of chewable tablet.	31
Ibuprofen	Polacrilin potassium, partially gelatinized starch, microcrystalline cellulose	Spray drying	Coprocessed excipient with good flow property and compression property is obtained from Polacrilin potassium, partially gelatinized starch and microcrystalline cellulose.	32
Rizatriptan Benzoate	Alpha lactose Monohydrate and maize starch.	Wet granulation	Coprocessing of lactose and maize starch produce final product with improved properties such as better compressibility, excellent flow and better disintegration.	33
-	Xylitol, starch and crospovidone.	Freeze drying Wet granulation	Coprocessed excipient prepared from xylitol, starch and crospovidone produces orally disintegrating properties and provide good mechanical strength.	34
-	Rice starch, monochloroacetic acid and sodium silicate	Spray drying	Excipient formed by coprocessing of rice starch shows good tensile strength with excellent flowability, good compressibility and disintegration properties.	35
Donepezil HCL	Microcrystalline cellulose and Mannitol. Maize starch and lactose. Microcrystalline cellulose and. lactose	Wet granulation	Coprocessing of plastic material (microcrystalline cellulose and maize starch) and brittle material (lactose and mannitol) produce modified excipient with good flow properties, compactability and disintegration properties. High dissolution rate observed in MCC and Mannitol (1:5) coprocessed excipient.	36
Atorvastatin calcium	Acacia mucilage and calcium carbonate	Wet granulation and	Excipient developed by coprocessing of acacia and calcium carbonate shows good flow, improved disintegration and dissolution properties are contributed to the presence of calcium carbonate.	37
Zolmitriptan	Lactose and sodium starch glycollate	Rotary evaporation	Lactose and sodium starch glycollate coprocessed excipient shows good orally disintegrating properties.	38
Venlafaxine HCL	Chitosan and Eudragit S-100	Solvent evaporation	Better release sustainability obtained from Excipient developed from coprocessing of chitosan and Eudragit S – 100.	39
Repaglinide	Microcrystalline cellulose, Aerosil and fenugreek seed mucilage.	Spray drying	Developed coprocessed excipient results in improved dissolution, flowability and compressibility.	41
Diclofenac sodium	Microcrystalline cellulose and Gaur gum Microcrystalline cellulose and Xamthum gum Microcrystalline cellulose and Almond gum Microcrystalline cellulose and gum of Kondagogu	Wet granulation	Coprocessed excipient from the mixture of microcrystalline cellulose and different gums in different ratio are prepared. Coprocessing of microcrystalline cellulose with Gaur gum in the ratio of 1:3 found to be better than other with release retarding property and good flow properties.	42
Montelukast	Sodium starch glycolate and Mannitol	Solvent evaporation	Modified excipient of sodium starch glycollate and Mannitol shows improved micromeritic properties and dissolution rate of 98.76%in 60 min.	43
Metronidazole Chloroquine Paracetamol	AvicelPH101, polyvinylpyrrolidone k15, partially gelatinized starch, magnesium stearate	Wet granulation	Multifunctional excipient with improved properties than the physical mixture of excipients prepared and found to be more effective.	44
Rizatriptan benzoate	Lactose and maize starch	Direct compression	Improved flow, disintegration, and compressibility	45

CONCLUSION:

The present article provide the information regarding excipient technology development and their approaches. Not a single excipient meets all requirements for producing novel drug delivery. Coprocessed excipient plays important role in developing dosage form which is stable and produce committed results. Modification of natural excipients is beneficial approach for production of excipients with improved properties and it is considered as a “generally regarded as safe”, as it involves only physical modification without any chemical alterations. It is also beneficial regarding cost.

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Received on 31.12.2020 Modified on 14.02.2021

Res. J. Pharma. Dosage Forms and Tech. 2021; 13(2):147-152.

DOI: 10.52711/0975-4377.2021.00026