Wet granulation is traditionally a batch process in the pharmaceutical production, however, the batch type wet granulations are foreseen to be replaced more and more by continuous wet granulation in the pharmaceutical industry in the future. The shift from batch to continuous technologies has been recommended by the Food and Drug Administration. Transforming from batch manufacturing to continuous manufacturing, to convert seam-lessly in fast continuous sequence, raw mate-rials into high-quality final products1,2. Continuous twin screw granulation and drying system during formulation development and process optimization.
Granulation, the process of particle enlargement by agglomeration technique, is one of the most significant unit operations in the production of pharmaceutical dosage forms, mostly tablets and capsules. Granulation process transforms fine powders into free-flowing, dust-free granules that are easy to compress. Nevertheless, granulation poses numerous challenges due to high quality requirement of the formed granules in terms of content uniformity and physicochemical properties such as granule size, bulk density, porosity, hardness, moisture, compressibility, etc. Together with physical and chemical stability of the drug. Granulation process can be divided into two types: wet granulation that utilize a liquid in the process and dry granulation that requires no liquid. The type of process selection requires thorough knowledge of physicochemical properties of the drug, excipients, required flow and release properties, to name a few. Among currently available technologies, spray drying, roller compaction, high shear mixing, and fluid bed granulation are worth of note.
Like any other scientific field, pharmaceutical granulation technology also continues to change, and arrival of novel and innovative technologies are inevitable. This review focuses on the recent progress in the granulation techniques and technologies such as pneumatic dry granulation, reverse wet granulation, steam granulation, moisture-activated dry granulation, thermal adhesion granulation, freeze granulation, and foamed binder or foam granulation. This review gives an overview of these with a short description about each development along with its significance and limitations.
IntroductionGranulation, a technique of particle enlargement by agglomeration, is one of the most significant unit operations in the production of pharmaceutical dosage forms, mostly tablets and capsules. During the granulation process, small fine or coarse particles are converted into large agglomerates called granules. Generally, granulation commences after initial dry mixing of the necessary powder ingredients along with the active pharmaceutical ingredient (API), so that a uniform distribution of each ingredient throughout the powder mixture is achieved.
Schematic diagram of tablet compression techniquesThe type of process selection requires thorough knowledge of physicochemical properties of the drug, excipients, required flow and release properties, etc. Granulation technologies like roller compaction, spray drying, supercritical fluid, low/high shear mixing, fluid bed granulation, extrusion/spheronization, etc. Have been successful for many decades in the preparation of various pharmaceutical dosage forms.
Pharmaceutical granulation technology continues to change, and various improved, modified, and novel techniques and technologies have been made available along the course. The aim of this review is to give the reader a glimpse of the latest techniques and technologies with regard to pharmaceutical granulation. Subsequently, this review gives a short description about each development along with its significance and limitations, which are summarized in. Recent progress in dry granulationDry granulation could be achieved either by roller compaction or by slugging. The two different types are illustrated in the schematic diagram. There has not been much progress in the dry granulation technique and technology in comparison to wet granulation, except for one important innovation known as pneumatic dry granulation technology developed by Atacama LabsOy (Helsinki, Finland), which is described below. The description of its significance and limitations are summarized in.
Pneumatic Dry Granulation (PDG)Pneumatic dry granulation (PDG), an innovative dry granulation technology, utilizes roller compaction together with a proprietary air classification method to produce granules with extraordinary combination of flowability and compressibility., In this method, granules are produced from powder particles by initially applying mild compaction force by roller compactor to produce a compacted mass comprising a mixture of fine particles and granules. The fine particles and/or smaller granules are separated from the intended size granules in a fractioning chamber by entraining in a gas stream (pneumatic system), whereas the intended size granules pass through the fractioning chamber to be compressed into tablets. The entrained fine particles and/or small granules are then transferred to a device such as a cyclone and are either returned to the roller compactor for immediate re-processing (recycling or recirculation process) or placed in a container for reprocessing later to achieve the granules of desired size., The schematic diagram of this process is represented as. Schematic diagram of pneumatic dry granulationPDG technology could successfully be used to produce good flowing granules for any formulations that produce compacts with a tensile strength of 0.5 MPa.
Also, this technology enables the use of high drug loads of up to 70-100%, because sufficient flowability could be achieved even at lower roll compaction forces (lower solid fractions) compared to usual roller compaction. In addition to these, this technology avails various other benefits such as faster processing speed, low cost, little or no material wastage, low dust exposure due to the closed nature of this unit, etc. However, the influence of recycling on the granule quality, suitability with low dose formulations, friability, etc. Remains a major issues regarding this technology. The description of its significance and limitations are summarized in.
Recent progress in wet granulationWet granulation is the widely used technique and the granules are produced by wet massing of the excipients and API with granulation liquid with or without binder. The steps involved in conventional wet granulation technique could be seen in. Wet granulation has witnessed various technical and technological innovations such as steam granulation, moisture-activated dry granulation or moist granulation, thermal adhesion granulation, melt granulation, freeze granulation, foamed binder or foam granulation, and reverse wet granulation. The significance and limitations of the recent wet granulation techniques and technologies are summarized in. Reverse wet granulationReverse wet granulation or reverse-phase wet granulation is a new development in the wet granulation technique that involves the immersion of the dry powder formulation into the binder liquid followed by controlled breakage to form granules. According to this invention, the binder solution was prepared initially and the dry powder excipients were added to the binder solution under mixing in granulator.
Alternatively, the drug was mixed with a solution of hydrophilic polymer and/or binder to form a drug-polymer/binder slurry as a granulating fluid. Granules were then formed by immersing a mixture of other dry excipients into the drug-polymer/binder slurry. The resulted wet granules were milled after drying.
The granules produced by this process were found to have good flow and handling characteristics like those produced with wet granulation process. In addition, tablets formed from these granules eroded more uniformly during dissolution testing as compared to usual wet granulation technique. The schematic diagram of this process is presented in.
Schematic diagram of reverse wet granulationControlled breakage was proposed to be the predominant granule formation mechanisms in reverse wet granulation technique., It is purported that this technique improves the dissolution characteristics of the poorly water-soluble drugs by allowing uniform distribution of the binder that acts as a wetting agent and enable adequate wetting of the drug substance during granulation. It also increases the chances of adequate and uniform contact between the drug and hydrophilic polymer for better dissolution. These improved granule characteristics result in even erosion of tablets during dissolution.,The advantages of this technique over conventional wet granulation include small and spherical-shaped granules with improved flow properties, uniform wetting and erosion of the granules. This technique could be suitable for poorly water-soluble drugs because of the intimate association between a drug and the polymer. Usability of currently available equipment such as high speed mixer is another merit of this technique. However, this technique produced granules with a greater mass mean diameter and lower intragranular porosity when compared to the conventional wet granulation at lower binder concentrations.
Steam GranulationIn steam granulation as a new wet granulation technique, water steam is used as binder instead of traditional liquid water as granulation liquid.shows the schematic diagram of steam granulation. Steam, at its pure form is transparent gas, and provides a higher diffusion rate into the powder and a more favorable thermal balance during the drying step. After condensation of the steam, water forms a hot thin film on the powder particles, requiring only a small amount of extra energy for its elimination, and evaporates more easily. Schematic diagram of steam granulationThe advantages of this process include the higher ability of the steam to distribute uniformly and diffuse into the powder particles, production of spherical granules with larger surface area, and shorter processing time ecofriendly (no involvement of organic solvents). An equipment such as high-shear mixer coupled with a steam generator would be enough for this technique. However, this method requires high energy inputs for steam generation.
Besides, this process is not suitable for all binders and is sensitive to thermolabile drugs. The granules produced by this process have higher dissolution rate due to increased surface area of the granules compared to conventional wet granulation process. Moisture-Activated Dry Granulation (MADG)This technique is a variation of conventional wet granulation technique.
It uses very little water to activate a binder and initiate agglomeration. This technique involves two steps, 1) wet agglomeration of the powder particles, and 2) moisture absorption or distribution. Agglomeration is facilitated by adding a small amount of water, usually less than 5% (1-4% preferably), to the mixture of drug, binder and other excipients. The two steps of this MADG are presented in. Agglomeration takes place when the granulating fluid (water) activates the binder. Once the agglomeration is achieved, moisture-absorbing material such as microcrystalline cellulose, silicon dioxide, etc.
Is added to facilitate the absorption of excess moisture. The moisture absorbents absorb the moisture from the agglomerates, resulting in moisture redistribution within the powder mixture, leading to relatively dry granule mixture. During this moisture redistribution process, some of the agglomerates remain intact in size without change, while some larger agglomerates may break leading to more uniform particle size distribution. It does not require an expensive drying step.
Schematic diagram of moisture-activated dry granulationThe process does not lead to larger lumps formation since the amount of water used is very small compared to usual wet granulation. The particle size of the agglomerates is mainly accounted to be in the range of 150-500 µm.
This technique is also known as “moist granulation technique” leading to confusions with the use of appropriate terminology. Some authors believe that dry granulation involves the use of a roller compaction or a slugging step followed by milling to obtain granules. However, this technique did not use either of those steps. Besides, given that this technique utilizes a small amount of water, the use of the term “dry granulation” would be inappropriate. Therefore, the authors believe that “moist granulation” would be an appropriate terminology for this technique. In either case, the technique is the same and this review uses the terminology “Moisture-Activated Dry Granulation (MADG)” coined by the inventors of this technique in 1987.The application of MADG to an immediate-release and controlled-release dosage forms showed the advantages of wet granulation such as increased particle size, better flow and compressibility., Additional advantages of this technique include wide applicability, time efficiency and less energy input, and involvement of few process variables with suitability of continuous process. However, this technique could not be used for the preparation of granules that require high drug load and for moisture sensitive drugs and hygroscopic drugs due to stability and processing problems associated with these types of drugs.
A high-shear mixer coupled with a sprayer would be a suitable equipment for the MADG process. An ideal machine should be equipped with efficient impellers, blades, and choppers to allow good mass movement and proper mixing of the granulation mass. Thermal Adhesion Granulation (TAG)Wei-Ming Pharmaceutical Company (Taipei, Taiwan) has developed this technique, and the thermal adhesion granulation, analogous to moist granulation, utilizes addition of a small amount of granulation liquid and heat for agglomeration. This is clearly presented in as a schematic diagram.
Unlike moisture activated dry granulation which uses water alone as granulation liquid, this process uses both water and solvent as granulation liquid. In addition to this, heat is used to facilitate the granulation process.
In this process, the drug and excipient mixture is heated to a temperature range of 30–130 °C in a closed system under tumble rotation to facilitate the agglomeration of the powder particles. This technique eliminates the drying process due to the addition of low amount of granulation liquid, which is mostly consumed by the powder particles during agglomeration. Granules of the required particle size can be obtained after cooling and sieving. Schematic diagram of thermal adhesion granulationThis technique is quite simple and convenient with low moisture and binder contents in a closed system for preparing highly compressible materials or for modifying the poor characteristics of excipients. Besides, this technique provides granules with better particle size, good flow properties and high tensile strength that could be directly compressed into tablets with adequate hardness and low friability. The limitations of this technique are requirement of considerably high energy inputs and special equipment for heat generation and regulation.
This technique is not suitable for all binders and is sensitive to thermolabile drugs. Melt granulationMelt granulation or thermoplastic granulation is a technique that facilitates the agglomeration of powder particles using meltable binders, which melts or softens at relatively low temperature (50–90 °C).represents the schematic diagram of melt granulation.
Cooling of the agglomerated powder and the consequent solidification of the molten or soften binder complete the granulation process., Low melting binders can be added to the granulation process either in the form of solid particles that melt during the process (melt-in procedure or in situ melt granulation) or in the form of molten liquid, optionally containing the dispersed drug (spray-on or pump-on procedure), which displays a variety of options to design final granular properties. More specifically, the melt-in procedure of melt granulation process includes heating a mixture of drug, binder and other excipients to a temperature within or above the melting range of the binder. On the contrary, the spray-on procedure encompasses spraying of a molten binder, optionally containing the drug, onto the heated powders. Schematic diagram of melt granulationMelt granulation is an appropriate alternative to other wet granulation techniques which are used for water sensitive materials. Moreover, in comparison with the conventional wet granulation process, it proposes several advantages., Generally, organic or aqueous solvents are not demanded for the melt granulation process, hence the environmental requirements of organic solvent capture and recycling are eliminated, while the absence of water excludes the wetting and drying phases, making the entire process less energy- and time-consuming. Melt granulation method could be efficiently applied in order to enhance the stability of moisture sensitive drug and further to improve the poor physical properties of the drug substance., The major drawback of this process is the need of high temperature during the process, which can cause degradation and/or oxidative instability of the ingredients, especially of the thermolabile drugs.The binders used for this process could be either hydrophilic or hydrophobic.
The selection of a meltable binder with a hydrophilic/hydrophobic feature is critical factor for the dissolution behavior of the drugs. The equipments that could be used for melt granulation are high-shear mixer and fluidized bed granulator.,- Interest in melt granulation has increased in recent years, owing to the numerous advantages of this technique over conventional wet granulation process. Freeze granulationFreeze granulation technology, spray freezing and subsequent freeze drying, involves spraying droplets of a liquid slurry or suspension into liquid nitrogen followed by freeze-drying of the frozen droplets. By spraying a powder suspension into liquid nitrogen, the drops are instantly frozen into granules, and in the subsequent freeze drying process, the granules are dried by sublimation of ice without any segregation effects.
The above-mentioned steps are depicted as schematic diagram in. This process yields spherical free-flowing granules that could be formed by using both water based and solvent based slurries.
The significance of this technology is that the structure and homogeneity of the particles in the slurry or suspension are retained in the granules. Although various kinds of material in dispersed form can be granulated using this technology, it is suitable for the preparation of fine powder mixes with proper additives for subsequent processing. Schematic diagram of freeze granulationThis technology could be useful for the preparation of granules that needs to be prepared from suspensions whose particle size and homogeneity need to be preserved. Eventually, re-dispersible parenteral formulations, nanomaterials, solid self-emulsifying drug delivery systems, etc. Could benefit from this technology given its ability to maintain size and homogeneity.
The suspension quality always determines and reflects the granule quality in terms of homogeneity. In pharmaceutical industry, the low-temperature and soft freeze drying has vital advantage to minimize damage of organic compounds and improve stability and/or solubility.