Co-Processed Excipients: New Era in Pharmaceuticals

 

Ashok Thulluru*, C. Madhavi, K. Nandini, S. Sirisha, D. Spandana

Sree Vidyanikethan College of Pharmacy, A. Rangampet, Tirupati-517102, Chittoor (Dist.), A.P., India.

*Corresponding Author E-mail: ashokthulluru@gmail.com

 

ABSTRACT:

Co-processing is the way that new excipients coming to the market without undergoing rigorous safety testing of completely as new chemical. It can be defined as combining two or more established excipients by an appropriate process. Co-processing of excipients could lead to formation of excipients with superior properties compared to simple physical mixtures of their components. The main aim of co processing is to obtain product with an added value related to the ratio of its functionality and / or price.

 

KEYWORDS: Co-processed excipients, formation, physical mixtures, established excipients.

 

 


INTRODUCTION:

Development of co-processed excipients starts with the selection of the excipients to be combined, their targeted proportion, selection of preparation method to get optimized product with desired physio-chemical parameters and it ends with minimizing avoidance with batch-to-batch variations. An excipient of reasonable price must be combined with the optimal amount of a functional material in order to obtain integrated product, with superior functionality than the simple mixture of components. Co-processing is interesting because the products are physically modified in a special way without altering the chemical structure. A fixed and homogenous distribution for the components is achieved by embedding them into mini granules.

 

Segregation is diminished by adhesion of the actives on the porous particles making process validation and in process control easy and reliable. The excipients industry to date has been an extension of the food industry1. Moreover, excipients are products of the food industry, which has helped to maintain a good safety profile. Increasing regulatory pressure on purity, safety, and standardization of the excipients has catalyzed the formation of an international body, the International Pharmaceutical Excipients Council (IPEC)2. IPEC is a tripartite council with representation from the United States, Europe, and Japan and has made efforts to harmonize requirements for purity and functionality testing3. The development of new excipients to date has been market driven (i.e., excipients are developed in response to market demand) rather than marketing driven (i.e., excipients are developed first and market demand is created through marketing strategies) and has not seen much activity as shown by the fact that, for the past many years, not a single new chemical excipient has been introduced into the market. The primary reason for this lack of new chemical excipients is the relatively high cost involved in excipients discovery and development. However, with the increasing number of new drug moieties with varying physicochemical and stability properties, there is growing pressure on formulators to search for new excipients to achieve the desired set of functionalities. Other factors driving the search for new excipients are:

·      The growing popularity of the direct‐compression process and a demand for an ideal filler–binder that can substitute two or more excipients3-5

·      Tableting machinery’s increasing speed capabilities, which require excipients to maintain good compressibility and low weight variation even at short dwell times.

·      Shortcomings of existing excipients such as loss of compaction of microcrystalline cellulose (MCC) upon wet granulation, high moisture sensitivity, and poor die filling as a result of agglomeration6

·      The lack of excipients that address the needs of a specific patient such as those with diabetes, hypertension, and lactose and sorbitol sensitivity. 

·      The ability to modulate the solubility, permeability, or stability of drug molecules.

·      The growing performance expectations of excipients to address issues such as disintegration, dissolution, and bioavailability7, 8.

 

Co-processing of Excipients:

The actual process of developing a co-processed excipient involves the following steps9:

1    Identifying the excipients group to be co-processed by carefully studying the material characteristics and functionality requirements.

2    Electing the proportions of various excipients.

3    Assessing the particle size required for co processing. This is especially important when   one of the components is processed in a dispersed phase. Post processing the particle size of the latter depends on its initial particle size.

4    Selecting a suitable drying process such as spray- or flash- drying optimizing the process (because even this can contribute to functionality variations). Fig.1. shows a schematic representation of the co-processing method10 and Table 1. Shows summary of various methods to prepare co-processed excipients10.

 

 

Fig.1. Diagrammatic representation of co-processing of excipients

 

 

Properties and advantages of the co-processed excipients:

Several authors have reported the advantages and possible limitations of the properties of co-processed excipients such as solidified microcrystalline cellulose (SMCC), Cellactose, and Ludipress.

 

 


 

Table1. Summary of various methods to prepare co-processed excipients

Method

Advantage and limitation

Example

Chemical modification

Expensive, time consuming, require toxicological data

Ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, lactitol, cyclodextrin from starch

Physical modification

Simple and economical

Sorbitol, dextrates and compressible sugars

Grinding or sieving

Compressibility may alter because of change in particle properties

Dibasic dicalcium phosphate, αlactose monohydrate

Crystallization

Impart flow ability to excipient but not self-binding properties, require stringent control on processing

Dipac, β-lactose

Spray drying

Spherical shape and uniform size give spray dried material good flowability, poor rework ability

Emdex, Avicel PH, advantose100, karion instants

Granulation/

agglomeration

Transfer poor flow, cohesive, small particle into flowable and directly compressible

Granulated lactitol, tablettose

Dehydration

Increase binding properties by thermal and chemical modification

Anhydrous α-lactose

 


a. Absence of chemical change:

Many detailed studies of excipients chemical properties after co-processing have proven that these excipients do not show any chemical change. Detailed studies of SMCC with X-ray diffraction analysis, solid-state nuclear magnetic resonance (NMR), IR spectroscopy, Raman spectroscopy, and C13 NMR spectroscopy have detected no chemical MCC11 changes and indicate a similarity to the physicochemical properties. This absence of chemical change helps reduce a company’s regulatory concerns during the development phase12.

 

b. Physico mechanical properties:

b.1. Improved Flow Properties:

Controlled optimal particle size and particle‐size distribution ensures superior flow properties of co-processed excipients without the need to add glidants. The volumetric flow properties of SMCC were studied in comparison with MCC. The particle‐size range of these excipients was found to be similar to those of the parent excipients, but the flow of co-processed excipients was better than the flow of simple physical mixtures. A comparison of the flow properties of Cellactose was also performed. The angle of repose and the Hausner’s ratio were measured, and Cellactose was found to have better flow characteristics than lactose or a mixture of cellulose and lactose13. The spray‐dried product had a spherical shape and even surfaces, which also improved the flow properties14.

 

b.2. Improved compressibility:

Co-processed excipients have been used mainly in direct compression tabletting because in this process there is a net increase in the flow properties and compressibility profiles and the excipient formed is a filler–binder15. The pressure– hardness relation of co-processed excipients, when plotted and compared with simple physical mixtures, showed a marked improvement in the compressibility profile. The compressibility performance of excipients such Cellactose16, SMCC17, 18 and Ludipress19 are superior to the simple physical mixtures of their constituent excipients. Although direct compression seems to be the method of choice for pharmaceutical manufacturing, wet granulation is still preferred because it has the potential advantages of increasing flow properties and compressibility when an extra granular binder introduced, and it achieves a better content uniformity in case of low‐dose drugs. Excipients such as MCC lose compressibility upon the addition of water, a phenomenon called quasihornification20. This property is improved, however, when it is co-processed into SMCC.

 

b.3. Better dilution potential:

Dilution potential is the ability of the excipient to retain its compressibility even when diluted with another material. Most active drug substances are poorly compressible, and as a result, excipients must have better compressibility properties to retain good compaction even when diluted with a poorly compressible agent. Cellactose is shown to have a higher dilution potential than a physical mixture of its constituent excipients21.

 

b.4. Fill weight variation:

In general, materials for direct compression tend to show high fill weight variations as a result of poor flow properties, but co-processed excipients, when compared with simple mixtures or parent materials, have been shown to have fewer fill‐weight variation problems. The primary reason for this phenomenon is the impregnation of one particle into the matrix of another, which reduces the rough particle surfaces and creates a near‐optimal size distribution, causing better flow properties. Fill‐weight variation tends to be more prominent with high‐speed compression machines. Fill‐weight variation was studied with various machine speeds for SMCC and MCC, and SMCC showed less fill‐weight variation than MCC.

 

b.5. Reduced lubricant sensitivity:

Most co-processed products consists of a relatively large amount of brittle material such as lactose monohydrate and a smaller amount of plastic material such as cellulose that is fixed between or on the particles of the brittle material22. The plastic material provides good bonding properties because it creates a continuous matrix with a large surface for bonding. The large amount of brittle material provides low lubricant sensitivity because it prevents the formation of a coherent lubricant network by forming newly exposed surfaces upon compression, thus breaking up the lubricant network.

 

b.6. Other properties: 

Co-processed excipients offer the following additional advantages23:

·      Pharmaceutical manufacturers have the option of using a single excipient with multiple functional properties, thereby reducing the number of excipients in inventory.

·      Improved organoleptic properties: Such as; Avicel CE15 (FMC Corp., Philadelphia, PA), which is a co-processed excipient of MCC, and guar gum were shown to have distinctive advantages in chewable tablets in terms of reduced grittiness, tooth packing and chalkiness. Over all improved mouth feel and palatability. 

·      The overall product cost decreases because of improved functionality and fewer test requirements compared with individual excipients.

·      Because they can retain functional advantages while selectively reducing disadvantages, co-processed excipients can be used to develop tailor‐made designer excipients.

·      This can be helpful in reducing the time required to develop formulations.

·      Co-processed excipients can be used as proprietary combinations, and in‐house formularies maintained by pharmaceutical companies, which could help in developing a formulation that is difficult to reproduce and provides benefits in terms of intellectual property rights.

 

Commercial status of co-processed excipients:

Many co-processed excipients have been launched in the market in the past few years, and a few formulations are commercially available.

 

Table 2. Lists some of the marketed co-processed excipients along with their manufacturers and benefits10.

 

Limitations of co-processed excipients:

Major limitation of co-processed excipient mixture is that the ratio of the excipients Major limitation of co-processed excipients are the ratio of the excipients in a mixture is fixed and in developing a new formulation, a fixed ratio of the excipients may not be an optimum choice for the API and the dose per tablet under development. Co-processed adjuvant lacks the official acceptance in pharmacopoeia. For this reason, a combination filler binder will not be accepted by the pharmaceutical mixtures of the excipients. Although the spray crystallized dextrose-maltose (Emdex) and compressible sugar are co-processed products as single components and are official in USP/NF.A regulatory perspective of the excipient mixtures with the absence of a chemical change during processing, co-processed excipients can be considered generally regarded as safe (GRAS) if the parent excipients are also GRAS-certified by the regulatory industry until it exhibits significant advantages in the tablet compaction when compared to the physical agencies. Hence, these excipients do not require additional toxicological studies. Excipient mixtures or co-processed excipients have yet to find their way into official monographs, which is one of the major obstacles to their success in the market place.

 

A regulatory perspective of the co-processed excipients:

With the absence of a chemical change during processing, co-processed excipients can be considered generally regarded as safe (GRAS) if the parent excipients are also GRAS-certified by the regulatory industry until it exhibits significant advantages in the tablet compaction when compared to the physical agencies. Hence, these excipients do not require additional toxicological studies. Excipient mixtures or co-processed excipients have yet to find their way into official monographs, which is one of the major obstacles to their success in the market place. The mixture of excipients was presented as a topic to the National Formulary and was assigned a priority on the basis of the use of the mixture in marketed dosage forms in which processing has provided added functional value to the excipient mixture.

 


 

Table2. Marketed co-processed excipients

Brand name

Adjuvant

Application

Advantages

Company, country

Cellactose

 

MCC,

Lactose

High-dosage tablet, herbal formulations

Highly compressible, good mouth feel, low cost

Meggle,

Germany

Pearlite SD

Granulated Mannitol

for chewable and effervescent tablet, Diluents for capsules and sachets may require higher level of lubricant (magnesium stearates)

_

 

Roquette,

 France

Ludipress

Lactose,

PVP, Crosspovidone

For use in chewable tablets andlozenges, foreffervescent tablets and as bulking agent for modified Release formulations.

good flowability, low hygroscopicity, hardness independent of machine speed

BASF,

Germany

Starlac     

Lactose,

maize Starch

_

Good flow

Roquette,

France

Pharmatose DCL 40

Anhydrous lactose, lactitol

_

 

High compressibility, low lubricant sensitivity

DMV,

Netherlands

Prosolv

 

MCC, colloidal Silica

_

better flow, hardness, reduced friability

Penwest,

USA

 


 

 

REFERENCES:

1.       Steinberg M, Blecher L. and Mercill A. From Inactive Ingredients to Pharmaceutical Excipients. Pharm. Technol. 2001; 25 (7): 62–64.

2.       IPEC‐Americas: Why IPEC‐Americas is needed. [Web link: http://www.ipecamericas.org.]

3.       Anuja Patil, VJ Kadam, KR Jadhav. Co-processed Pharmaceutical Excipients – A Brief Review. Research J. Pharm. and Tech. 2010; 3(1): 50-57.

4.       B. Soujanya, G. Pavani Priya, T.E.G.K. Murthy.Co-Processing of Excipients: A Review on Excipient Development for Improved tabletting Performance. Res. J. Pharm. Dosage Form. and Tech. 2015; 7(2): 149-155.

5.       P. Lakshmi, K. Pramod, K.C. Ajithkumar. Co-Processed Excipients for Tabletting. Res. J. Pharm. Dosage Form. and Tech. 2016; 8(1): 46-54.

6.       Blecher L. Pharmaceutical Excipients: Producers and Users Strengthen their Voice. Pharm Technol. 1993; 17 (2): 38–39.

7.       Amit Alexander, Ajazuddin, D K Tripathi, Tekeshwar Verma, Sandip Patel, Harsh Deshmukh, Swarna. Role of Excipients to Enhance the Disintegration Property of Different Formulations: An Overview. Research J. Pharm. and Tech. 2011; 4(10): 1519-1525.

8.       Sandesh Narayan Somnache, Ajeet Madhukar Godbole, Pankaj Sadashiv Gajare, Sapna Kashyap. Significance of Pharmaceutical Excipients on Solid Dosage form Development: A Brief Review. Asian J. Pharm. Res. 2016; 6(3): 193-202.

9.       Amol Main, B. A. Bhairav, R. B. Saudager. Co-processed Excipients for Tabletting: Review Article. Research J. Pharm. and Tech. 2017; 10(7): 2427-2432.

10.     Sreekanth Babu S, Ajay Kumar A, Suman D R. Co-Processed Excipients: A Review. International Journal of Current Trends in Pharmaceutical Research. 2013; 1(3): 205-214.

11.     M.J. Tobyn et al. Physicochemical Comparison between Microcrystalline Cellulose and Silicified Microcrystalline Cellulose. Int. J. Pharm. 1998; 169: 183–194.

12.     Rajendra Jangde, Rahul Singhour, SJ Daharwal. Compatibility Studies Between Gatifloxacin and Pharmaceutical Excipients through Differential Scanning Calorimetry and Infra Red Spectroscopy. Research J. Pharma. Dosage Forms and Tech. 2010; 2(1):103-106.

13.     York P. Crystal Engineering and Particle Design for the Powder Compaction Process. Drug Dev. Ind. Pharm. 1992; 18 (6, 7): 677–721.

14.     T. Sonica, T. E. G. K. Murthy. Studies on the Influence of Different Co processing Excipients on the Flow and Dissolution kinetics of Donepezil HCl. Research J. Pharm. and Tech. 2013; 6(8): 868-873.

15.     R.K.V. Naga Sudha, G. Padmini, T.E.G.K. Murthy. Development of Novel Co-Processed Excipients for the Design and Evaluation of Directly Compressible Tablets of Rizatriptan Benzoate. Res. J. Pharm. Dosage Form. and Tech. 2015; 7(1): 07-10.

16.     Belda PM, Mielck JB. The Tableting Behavior of Cellactose Compared with Mixtures of Celluloses with Lactoses. Eur. J.Pharm. Biopharm. 1996; 42 (5): 325–330.

17.     Sherwood BE, Becker JW. A New Class of High Functionality Excipients: Solidified Microcrystalline Cellulose. Pharm. Technol. 1988; 22(10): 78–88.

18.     Allen JD. Improving DC with SMCC. Manufacturing Chemist. 1996; 67 (12): 19-23.

19.     Schmidt PC and Rubensdorfer CJW. Evaluation of Ludipress as a Multipurpose Excipient for Direct Compression Part I: Powder Characteristics and Tableting Properties. Drug Dev. Ind. Pharm. 1994; 20 (18): 2899–2925.

20.     Staniforth JN and Chatrath M. Towards a New Class of High Functionality Tablet Binders: Quasi‐Hornification of Microcrystalline Cellulose and Loss of Functionality. Pharm. Res. 1996; 13 (9): 208.

21.     Flores LE, Arellano RL, and Esquivel JD. Study of Load Capacity of Avicel PH‐200 and Cellactose, Two Direct‐Compression Excipients, Using Experimental Design. Drug Dev. Ind. Pharm. 2000; 26 (4): 465– 469.

22.     Maarschalk KVDV and Bolhius GK. Improving Properties of Material for Direct Compaction. Pharm. Technol. 1999; 23 (5): 34–46.

23.     K. Venkata Ramana Reddy, K. Divakar, B. Venkateswara Reddy, P. Shruti. Pharmaceutical Excipients- Their Mechanisms. Research J. Pharma. Dosage Forms and Tech. 2013; 5(6): 355-360.

 

 

 

Received on 19.01.2019                Modified on 28.01.2019

Accepted on 15.02.2019            © A&V Publications All right reserved

Asian J. Res. Pharm. Sci. 2019; 9(1):01-05.

DOI: 10.5958/2231-5659.2019.00001.8