Handbook of Pharmaceutical Granulation Technology

Dilip M. Parikh

• Publisher: CRC Press
• Year: 2021
• ISBN:
  9781000366402
• Edition: 4
• Topic: Medicina
• Subtopic: Farmacología

This fully revised edition of Handbook of Pharmaceutical Granulation Technology covers the rapid advances in the science of agglomeration, process control, process modelling, scale-up, emerging particle engineering technologies, along with current regulatory changes presented by some of the prominent scientist and subject matter experts around the globe. Learn from more than 50 global subject matter experts who share their years of experience in areas ranging from drug delivery and pharmaceutical technology to advances in nanotechnology. Every pharmaceutical scientist should own a copy of this fourth edition resource.

Key Features:

• Theoretical discussions covering granulation and engineering perspectives.
• Covers new advances in expert systems, process modelling and bioavailability
• Chapters on emerging technologies in particle engineering
• Updated Current research and developments in granulation technologies

1	Introduction

Dilip M. Parikh

CONTENTS

1.1 Introduction

1.2 Need for Granulating Powders

1.3 Granulation Options

1.4 Developments in Processing Solid Dosage Forms

1.5 Scope of This Book

References

1.1 Introduction

Solid-dosage forms encompass the largest category of dosage forms that are clinically used. Several types of tablet solid dosage forms are designed to optimize the absorption rate of the drug, increase the ease of administration by the patient, control the rate and site of drug absorption, and mask the taste of a therapeutic agent. This also applies to the capsules of various sizes and various release profiles. The formulation of tablets and capsules involves the use of several components, each of which is present to facilitate the manufacture or to control the biological performance of the dosage form. The practice of delivering medicinal powder by hand rolling into a pill by using honey or sugar has been used for centuries. The delivery of some of the botanical and herbal extracts in homeopathic and ayurvedic branches of medicine by rolling into a pill is still practiced in India along with allopathic medicine.

1.2 Need for Granulating Powders

Processing powders in the industry is a challenge. Particularly in the chemical and pharmaceutical industries as different powders are mixed there to make a solid dosage form such as tablets, capsules, and pellets. It becomes even more critical since the segregation of different ingredients can create a dosage form, which may result in variability in the final product quality attributes. Segregation of powders is due primarily to differences in the size or density or flow properties of the components of the mix. If the product composition has a desirable flow and non-segregating properties, it can be directly compressed or encapsulated. For powder mixture to be homogeneous, the composition of the mix should have complementary physical properties, such as flow, particle size, and morphology. Where drug substance dosage is high and has a poor flow property, and a larger quantity of excipients are needed to facilitate the direct compression, the resulting dosage form may be larger, and thus may not be normally unacceptable due to the difficulty of swallowing such a large tablet. The decision on whether to opt for a granulation operation should also be based on the knowledge of the potential disadvantages associated with employing the direct compression of the powdered mix. Failing these physical attributes, dry or wet granulation should be considered. Granulation is a process of size enlargement used primarily to prepare powders for tableting. It consists of homogeneously mixing the drug and excipients and then wetting them in the presence of a binder so that larger agglomerates or granules are formed. An ideal granulation should contain all the constituents of the mix in the correct proportion in each granule, thus the segregation of the ingredients will not occur.

An earlier mention of granulating medicine cited in 1773, by Thomas Skinner in Duncan’s Elements of Therapeutics in 1862 as follows: “by the application of art, it is intended that medicines should be rendered more agreeable, more convenient, safer and more efficacious than they are in their natural state. To obtain these ends is the intention of pharmacy.” Skinner further describes the earlier method of making granules by French pharmacists who had a form of medication that they call “poudres granules.” Perry’s Chemical Engineer’s Handbook [1] defines the granulation process as “any process whereby small particles are gathered into larger, permanent masses in which the original particles can still be identified.” This definition is appropriate to a pharmaceutical granulation where the rapid breakdown of agglomerates is important to maximize the available surface area and aid in the solution of the active drug. The granulated material can be obtained by direct size enlargement of primary particles or size reduction from dry, compacted material.

In the pharmaceutical field, solid dosage forms remain an important part of the overall drug market, despite the success and the development of new pharmaceutical forms. The high risk of failure in drug discovery and development throughout the pharmaceutical industry statistically shows that, on average, only 1 in 5000 compounds screened in research will reach the market. The new drug approvals for 2018 and 2019 show predominant approvals are for solid dosages. For example for 2018, out of 59 total approvals listed on the FDA website, 31 approvals are for either tablets, capsules, or powders, while for the year 2019, there were a total of 48 novel drug approvals, with 5 new formulations and 7 new dosage forms using the technologies described in this book. In 2019, The Center for Drug Evaluation and Research (CDER) approved 48 novel drugs. The ten-year graph below shows that from 2010 through 2018, CDER has averaged about 37 novel drug approvals per year. A number of these approvals are for the solid dosage forms [2], (Figure 1.1).

Figure 1.1 FDA. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2019.
Source: From Ref. [2].

CDER identified 20 of the 48 novel drugs approved in 2019 (42%) as first-in-class, which is one indicator of the drug’s potential for a strong positive impact on the health of the American people. These drugs often have mechanisms of action different from those of existing therapies.

Similarly, global spending on cancer medicines – both for therapeutic and supportive care use – rose to $133 billion globally in 2017, up from $96 billion in 2013. It is predicted that the global market for oncology therapeutic medicines will reach as much as $200 billion by 2022 [3].

1.3 Granulation Options

Several products cannot be directly compressed because of the low dosage of drug substance, or flow properties of the drug and excipient mixture. The formulation containing such a low dose could be challenging to meet the bioavailability or content uniformity. Several other reasons why direct compression may not be suitable for a wide array of products include the required flow properties; dissimilar ingredient physical attributes, such as particle size, morphology, moisture content and the content of each excipient in the formulation form; requirement of densification to reduce the size of the drug product, obtain the required hardness, friability, and disintegration/dissolution; and others. The final quality attributes of the dosage form will be based on the process of technology to be employed. The selection of the process also entails ancillary equipment that could have an impact on the granule properties; hence, characterizing the granulation for its flowability, morphological properties, and impact on bioavailability is necessary.

Many researchers studied the influence of material properties of the granulating powders and process conditions on the granulation process in a rather empirical way. In the 1990s, a fundamental approach to research was started on various topics in the granulation process, looking into more detailed aspects of particle wetting, mechanism of granulation, material properties, and influence of mixing apparatus on the product. The overall hypothesis suggested that the granulation can be predicted from the raw material properties and the processing conditions of the granulation process. One of the major difficulties encountered in the granulation technology is the incomplete description of the behavior of powders in general. The ongoing fundamental research on mixing, segregation mechanisms of powder, surface chemistry, and material science is necessary to develop the theoretical framework of granulation technology. An excellent review of the wet granulation process was presented by Iveson and coauthors [4]. They have advanced the understanding of the granulation process by stating that there are three fundamental sets of rate processes that are important in determining wet granulation behavior. These are wetting and nucleation, consolidation and growth, and breakage and attrition. Once these processes are sufficiently understood, then it will be possible to predict the effect of formulation properties, equipment type, and operating conditions of granulation behavior, provided these can be adequately characterized according to the reviewers. The most widely used granulation technologies that are used in the industry are shown in Figure 1.2. As can be seen, making granules from powders provides several different options.

Figure 1.2 Granulation Options (copyright DM Parikh).

With the development of rotary tablet presses in the 19th century initially and the advent of high-speed compression and encapsulation machines requiring production rates, the demand for free-flowing powders and granules has increased substantially. In the pharmaceutical industry, the simplest form of solid dosage form employs granules prepared from the drug and other components in stable aggregates in sizes large enough to facilitate the accurate formulation and dispensing for the subsequent processing. For a pharmaceutical solid dosage form, the granulation process is the first unit operation that needs to be carefully planned. The excipient variability is well known in the industry. All of the excipients necessary for the robust formulation usually meet all the compendial requirements, but more often the particle size and morphology consistency from batch to batch do not. Physical properties of excipient, as well as API, should be consistent from batch to batch, as one of the requirements to develop a robust formulation that will reduce final dosage form variability. This requirement has become even more critical as the industry has started to adopt continuous granulation technology.

Dry compaction technique like roller compaction is experiencing a renewed interest in the industry. The roller compaction processes and equipment were adapted and modified from other industries like metal, mineral, and recycling industries. In the early 19th century, the process was utilized in the mining industry to crush rocks for easy extraction of desired precious material. In the mid-20th century, the process was used to compress pharmaceutical powders. Several drug substances are moisture sensitive. The roller compaction process provides suitable alternative technology for granulating these products. It offers advantages compared with wet granulation for processing physically or chemically moisture-sensitive materials since a liquid binder and thus drying of granulation is not required. This technology can also be used to produce effervescent granulations. The current offering of this technology is equipped with process analytical tools (PATs) that provide process monitoring and help in scale-up and optimization.

In the wet granulation process, primary particles of drug and excipient mixture granulated with either water, alcohol, or mixture of water and alcohol are the choice of binder. Four key mechanisms outlined by Ennis [5,6] are for the agglomeration of particles, that were subsequently further developed by Litster and Ennis [7]. These include wetting and nucleation, coalescence or growth, consolidation, and attrition or breakage. Initial wetting of the feed powder and existing granules by the binding fluid is strongly influenced by spray rate or fluid distribution as well as feed formulation properties, in comparison with mechanical mixing.

Early stages of wet granulation technology development employed low-shear mixers, or the mixers/blenders normally used for dry blending such as ribbon mixers. There are several products currently manufactured using these low-shear granulators. However, as process control and efficiency have increased over the years; the industry has embraced high-shear granulators for wet granulation because of its efficient process reproducibility and modern process control capabilities. The high-shear mixers have also facilitated new technologies, such as one-pot processing, that use the mixer to granulate and then dry in the same unit, the wet mass, using a vacuum, gas stripping/vacuum, or microwave-assisted vacuum drying. The high-shear one-pot system can be utilized for granulating potent compounds or to produce effervescent granulation. The one-pot system has an advantage especially where an organic solvent is used. It reduces the footprint and minimizes the number of process equipment. The fluid bed processing of powders is a well-established technology. Previously fluid bed processors were used only as a dryer but now it has become a multiprocessor, where granulation, drying, particle coating, taste masking, and pelletization processes can be performed.

1.4 Developments in Processing Solid Dosage Forms

For both small molecules and biopharmaceuticals, more sophisticated drug delivery systems are being developed to overcome the limitations of conventional forms of drug delivery systems (e.g., tablets and intravenous [IV] solutions), problems of poor drug absorption, noncompliance of patients, and inaccurate targeting of therapeutic agents. Futuristic drug delivery systems are being developed, which are hoped to facilitate the transport of a drug with a carrier to its intended destination in the body and then release it there. Liposomes, monoclonal antibodies, and modified viruses are being considered to deliver “repair genes” by IV injection to target the respiratory epithelium in the treatment of cystic fibrosis. These novel drug delivery systems not only offer clear medical benefits to the patient but can also creat...

Table of contents

• Cover
• Half Title
• Series Page
• Title Page
• Copyright Page
• Dedication
• Contents
• Preface
• Editor
• Contributors
• Chapter 1 Introduction
• Chapter 2 Theory of Granulation: An Engineering Perspective
• Section I: Particle Formation
• Section II: Granulation Processes
• Section III: Product-Oriented Granulations
• Section IV: Characterization and Scale-UP
• Section V: Optimization Strategies, Tools, and Regulatory Considerations
• Index