Introduction

Dosage forms of pharmaceutical substances contain pharmacologically active compounds and excipient additives to support the formulation and manufacturing for patient administration. The final dosage form specification, particularly regarding stability and bioavailability, depends on the choice of excipients, their concentrations, and interactions with the active compound and between each other [1]. An excipient of inactive substances is preferable which can be used as a carrier for the medication’s active ingredients. Moreover, excipients can be used to facilitate the manufacturing process [2]. The International Pharmaceutical Excipients Council (IPEC) has defined excipients as “inactive vehicle medium substance that serve for a drug or other active substance which is safe and intentionally formulated with the system of drug delivery”. Excipients, for example, can (a) aid in drug delivery processing during the manufacturing process; (b) support, protect, and stability-enhancing, bio-availability and also acceptable by the patient; (c) Product identification assisting; and (e) Further attributed enhancement of effectiveness, safety, or drug delivery of the shelf life and during use [3]. The excipients industry is an extension of the food industry  [4,5]. Excipients have recently been considered inactive ingredients. pharmaceutical scientists, with time, consider that excipients are not inactive. They frequently show a significant impact on the manufacturing process in aspects of safety, quality, and efficacy of the drug substances of the dosage form. The performance variability of excipients shows an impact on the batch-to-batch within a single manufacturing process and manufacturers and also between several batches of different manufacturers arises an understood as a key determinant of dosage form performance [6]. The medicine dosage form, regardless of the composition or mode of use, should comply with the following requirements that underpin safety, efficacy, and quality; (a) contain an accurate dose; (b) be taken or administered conveniently; (c) the drug may in a form for absorption or other delivery way to the target; (d) remain same quality during shelf-life and period of usage; and (e) manufacturing process does not compromise performance and is reproducible and economically acceptable [7]. Tablet manufacturing was changed by two introductions, the direct-compression process with high-speed machining. Both of these developments increase demand for the excipient’s functionality in terms of flow and compression properties. Solid handling engineering of individual excipients and combinations excipients using co-processing by several kinds of particle modifications need to provide an attractive tool for the development of high-functionality excipients which are fit with modern tablet manufacturing processes [8]. Most formulations contain a higher content of excipients compared to the active ingredient as a consequence the excipients may play a major role in controlling the formulation’s functionality and processability  [9]. The ideal method of tablet manufacturing is the compression process  [10]. A comprehensive study in this work addressed an issue of excipients with their interaction with active ingredients in pharmaceutical industries which is not been well reported in the literature previously.

Experimental

Hypothesis and objectives

The main objective of this work is a new excipient development associated with excipient co-processing and a novel excipient. A full study of the physical properties of newly prepared excipients in the aspect of formulation, stability, particle size, and mixing efficiency to lead to reduction of the manufacturing process.            

Development of new excipient

The development of new excipients does not show much activity as observed over the recent years, not even a single excipient material was introduced to the market [11]. The main reason is attributed to the high cost involved in excipients discovery and development. An increasing number of new drug moieties with varying physicochemical and stability properties led to growing pressure on formulators to find new excipients that can achieve well-desired functionalities [12]. A new excipients mixture through co-processing of two or more existing excipients is coming into the market without undergoing the rigorous safety testing of completely new chemicals. This method is interesting due to the products being modified physically in several ways without altering the chemical structure [13]. The co-processing is intensively explored for the direct preparation of compressible adjuvants due to its cost-effectiveness and can be prepared in-house upon the functionality requirement. The present work is focused on the properties of the co-processed compressible adjuvants which are available in the market [14]. The present usage of term “direct compression” is used to refer to the process by which tablets are compressed directly from powder blends of active ingredients and suitable excipients. No pre-treatment for powder blends using wet or dry granulation is involved [15]. Co-processing is attractive because the products are physically modified especially without altering the chemical structure. A fixed and homogenous component for the formulation can be achieved by embedding them within the fine powder. Segregation is diminished due to the adhesion of the actives on the porous particles making the process validation and in-process control easy and reliable [16]. A co-processed excipient is a mixture containing more than one excipient and not prepared by simple physical mixing. These materials are formulated with co-grinding, co-crystallization, co-precipitation, spray drying, and common solvent evaporation. The physical properties namely size, shape, and density of particles, may differ from one excipient to another resulting in segregation and non-uniformity [17]. Solid oral dosage forms, namely tablets and capsules, are the most common form of drug product of pharmaceutical manufacture [18]. Tablets and capsules contain the API and excipients. The excipients play several roles including fillers, binders, disintegrates, glidants, and lubricants [19]. The tablet formulation involves several components, each of which is present to facilitate the manufacture or to control the biological performance of the dosage form [20].

Method

The materials used in this study were divided into two types, the active pharmaceutical ingredient (APIs) which is a part of the pharmaceutical dosage form that produces the intended effects, and the inactive ingredients (excipients) which are any component of the pharmaceutical medication other than the active ingredient.

Active pharmaceutical ingredient

The active substances in the study were selected so that their concentrations vary in dosage form, from low concentrations that do not exceed 5%, such as bisoprolol, to high concentrations exceeding 70%, such as ciprofloxacin. The active ingredient for the formulation is listed in Table 1.

Inactive ingredients

The adjuvants were selected from among the available, inexpensive and multi-use materials in the pharmaceutical industry. These materials are either used in the formula of co-processed excipient, or the preparation of the new excipient but not used in the formula where the use of purified water and ethanol, or used to add the step of compression in case of low flowability of some high concentrated dosage forms (e.g., magnesium stearate as a lubricant), The inactive ingredients for this formulation is presented in Table 2.

 Method of preparation of co-processed excipients

For each preparation run, the following wet granulation steps were followed: The weighing: each material was weighed in a clean polyethylene bag using a calibrated digital balance. Mixing: Each material was added to a clean Polyethylene bag and the powder mixture was mixed manually for 5 minutes. Wet massing: The powder mixture was put in a stainless steel drum and the granulation liquid (purified water or ethanol) was added gradually and was stirred by using a glass rod till distinct granules were formed and the fine powder disappeared. Granulation: The wet mass was granulated by using a sieve size of 2 mm, and batch was passed through the sieve.

drying

 The formulation prepared using purified water was dried for 24 hours at 50 ^οC using a conventional oven as a dryer, whereas the formulation prepared by using ethanol 96% was dried for 8 hours at 50^οC using a conventional oven as a dryer. Sizing: The granulation was sized to the required size by using the suitable sieve; all dried granules were passed through sieve No. 25 (0.71 mm).         

Preparation of co-processed excipients

The preparation of co-processed excipients was according to the formulations listed in Table 3. A different macro close concentration was prepared and presented in Table 4.

Evaluation of the co-processed excipients

Evaluation of co-processed excipient was according to the following standard methods, namely compressibility; followability by Hausner ratio and compressibility index; granule size; and moisture content, as depicted Figure 2.

Tablet preparation using the co-processed excipient

Direct compression method was used as per the steps of, weighing: Each material was weighed in a clean polyethylene bag alone using a digitally calibrated balance, Mixing: The materials were added to a clean Polyethylene bag and the powder mixture was mixed manually for 5 minutes, Compression: The formulation was compressed using the specified punch, weight and hardness were controlled as the required specification.

Tablets prepared from different macrolose preparations

Batches (150 tablets /batch) of meloxicam 15 mg tablets were prepared with different combinations of macrolose, CL-1 to CL-16 and 0.5% of magnesium stearate as lubricant. The only variable in the batches was the type of macrolose.

Active substances formulated with macrolose

Macrolose co-processed excipient was compressed alone as a placebo and with different drug substances with different strengths and physicochemical proportions, as summrized in Table 5.

Evaluation of tablets

To evaluate the functionality of the co-processed excipient, tablets were formulated from the active material and co-processed excipient. Randomly selected tablets were subjected to physical tests such as weight variation, hardness test, friability test, disintegration test, and thickness test according to USP 2010 [21,22].

Method for evaluation of macrolose

The macrolose powder was taken and specified visually to describe the powder. The moisture content of each batch was tested. The powder of each batch was prepared for compression with Meloxicam as per the formula in Table 4. The parameter of Meloxicam 15 mg was prepared and the specification of the formula is listed in Table 6.

The compressed tablets were tested to evaluate macrolose with the tests of weight variation, hardness test, friability, disintegration and thickness of the tablet, as provided in Table 7.

Stability conditions and packaging

An accelerated stability study was carried out at a temperature of 40±2 ^οC and Relative Humidity of 75%±5%. The samples were tested for 6 months. The real-time stability study was carried out at a temperature 30±2 ^οC and Relative Humidity of 65%± 5%. The samples were tested at the 3^rd and 6^th month of stability. The samples were packed primarily in transparent polyethylene bags. The secondary packs were white, high-density polyethylene (HDPE) plastic containers, of microlose density, as displayed in Figure 1. The physical test involving several basic parameters was conducted and the result is listed in Table 8.

Particle size analysis of macrolose

Macrolose CL-16 particle sizes were determined using sieves in deferment mesh, as indicated in Table 9 and Figure 3. Particle size distribution is presented in Figure 4.    

Macrolose was a combination of Lactose monohydrate and Microcrystalline Cellulose (MCC). To ensure good mixing and better control of particle size, the method of preparation was wet granulation. The combination of MCC and lactose gave a good formulation as DC filler for tablet compression, so meloxicam tablets were compressed by using Macrolose batches CL-1 to   CL-5 and passed the appearance, hardness and friability tests, as presented in Table 3. Tablets were physically evaluated and Cl-4 was taken as the best formulation. CL-4 was further optimized (CL- 6 – CL-10). All formulations showed variation in disintegration time. When 4% sodium starch glycolate was added (CL-11) the resultant tablets were lower in hardness and more friable, Table 4. A new formulation was prepared by taking CL-3 as a base formula and 4% sodium starch glycolate was added (CL-12). The tablets produced complied with the compendia specifications. Based on the above experiments, CL-12 was taken as the best-optimized co-processed excipient. A large batch of the same formulation was prepared (CL-16-I) from which, eight different active pharmaceutical ingredients of different strengths were prepared by the DC method. The produced tablets showed a very high dilution potential of the new excipient macrolose (57%), as indicated in Table 5. The evaluation of different tablets prepared was by BP2011 and USP 2010 requirements. For the stability study, all the QC parameters were within the limits from zero time up to 6 months of accelerated and real-time stability studies.

Conclusion

To sum up, the new co-processed excipient, macrolose, has successfully met most of the study's objectives and has demonstrated superiority over existing excipients. The active pharmaceutical ingredients used in Tables 4 and 5 ranged from 5 mg to 400 mg, which showed the high dilution potential of macrolose which reached 57%, while the best dilution factor of DC materials is 25%. The QC results demonstrated that the new co-processed excipient macrolose is useful DC multifunctional filler for producing cost-effective, safe and effective pharmaceutical products.

Recommendation

• Macrolose should undergo further advanced studies, including a full stability study, compressibility tests, and all physical tests with various active ingredients. In addition, large-scale batches should be prepared to assess its production feasibility for multiple types of drugs.
• Commercial production of macrolose for producing cost-effective drug products is recommended.
• Further studies is suggested on macrolose with different particle sizes and moisture content are recommended.

Acknowledgements

The authors express their gratitude for the University of Al-Ameed.

Funding

Self-support.

Authors’ Contributions

All authors are equally contributed in preparing this article.

Institutional Review Board Statement     
Not applicable.

Informed Consent

Not applicable

Data Availability

Data available on reasonable request

Conflicts of Interest

All authors declare that there is no conflicts of interest in this article.

Orcid:

Ali Thoulfikar A. Imeer: https://orcid.org/0000-0003-0842-1072

Abdulkareem Mohammed: https://orcid.org/0000-0001-9133-2884

Abdul Amir H. Kadhum: https://orcid.org/0000-0003-4074-9123

Ahmed A. Al-Amiery: https://orcid.org/0000-0003-1033-4904

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How to cite this article: Abdullah Fadel Al-Mesbahi, Hassan Thulfikar, Ali Thoulfikar A. Imeer, Abdulkareem Mohammed, Abdul Amir H. Kadhum, Ahmed A. Al-Amiery, Evaluation of multifunctional co-processed excipient improvement of tableting performance.  Journal of Medicinal and Pharmaceutical Chemistry Research, 2024, 6(9), 1289-1300. Link: https://jmpcr.samipubco.com/article_193603.html

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Copyright © 2024 by SPC (Sami Publishing Company) + is an open access article distributed under the Creative Commons Attribution License(CC BY)  license  (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.