A Review of Hot Melt Extrusion Process Technology to Pharmaceutical Products

1. Introduction

To date HME has emerged due to a good novel processing technology in growing molecular dispersions of active pharmaceutical materials (APIs) into several polymer or/and lipid matrices which has led this approach to demonstrate period controlled, modified, extended, and targeted medicine delivery [1-4]. HME has provided opportunity for usage of materials as a way to mask the bitter preference of active substances. Since the industrial program of the extrusion procedure back the 1930¡¯s, HME has received considerable interest from both the pharmaceutical sector and academia in a range of applications for pharmaceutical dosage forms, such as tablets, capsules, films, and implants for medication delivery via oral, transdermal, and transmucosal routes [5]. This makes HME an excellent alternative to other conventionally obtainable techniques such as roll spinning and spray drying. In addition to being a proven manufacturing method, HME meets the purpose of the US Food and Medication Administration¡¯s (FDA) procedure analytical technology (PAT) scheme for designing, analyzing, and controlling the developing process via top quality control measurements during productive extrusion process [6]. In this chapter, the hot-melt extrusion strategy is reviewed based on a holistic perspective of its various factors, processing technologies, and the substances and novel formulation developments and design in its varied applications in oral drug delivery systems.

2. Procedure Technology of Hot-Melt Extrusion (HME)

Hot-melt extrusion approach was first invented for the making of lead pipes by the end of the eighteenth century [7]. Since that time, it has been used in the plastic material, rubber, and foodstuff manufacturing industry to produce items which range from pipes to bed sheets and bags. With the arrival of large throughput screening, currently more than half of most plastic products including bags, bed sheets, and pipes are constructed my HME and therefore various polymers have already been utilized to melt and create different shapes for a variety of commercial and domestic applications. The technology (HME) has shown to be a robust approach to producing numerous medication delivery systems and for that reason it's been found to end up being useful in the pharmaceutical market as well [8]. Extrusion is the procedure for pumping recycleables at elevated controlled temperatures and pressure through a heated barrel into a merchandise of uniform condition and density [9]. Breitenbach first introduced the development of melt extrusion procedure in pharmaceutical manufacturing functions [10]; nevertheless, Follonier and his coworkers earliest examined the hot-melt technology to produce sustained launching polymer-based pellets of varied freely soluble drugs [11]. HME requires the compaction and conversion of blends from a powder or a granular mix right into a merchandise of uniform shape [9]. During this process, polymers are melted and shaped into goods of different shapes and sizes such as plastic bags, linens, and pipes by forcing polymeric parts and active substances including any additives or plasticisers via an orifice or die under controlled temperature, pressure, feeding fee, and screw speed [9, 12]. On the other hand, the theoretical method of understanding the melt extrusion procedure (Figure 1) could be summarized by classifying the whole process of HME compaction in to the following [13]:(1)feeding of the extruder through a hopper,(2)mixing, grinding, lowering the particle size, venting, and kneading,(3)circulation through the die, and(4)extrusion from the die and additional downstream processing.

Amount 1: Schematic diagram of the HME process [12].

The extruder generally consists of a couple of rotating screws (either corotating or counter rotating) in the stationary cylindrical barrel. The barrel is normally often manufactured in sections so that you can shorten the home time of molten resources. The sectioned elements of the barrel are bolted or clamped in concert then. An end-plate die is connected to the finish of the barrel that is determined based on the shape of the extruded materials.

3. Twin-Screw and single-screw Extruder

A single-screw extruder consists of one rotating screw positioned in the stationary barrel at the most fundamental level. In the more advanced twin-screw systems, extrusion of materials is conducted by the counter-rotating or corotating screw configuration [9]. Regardless of type and complexity of the function and process, the extruder should be with the capacity of rotating the screw at a picked predetermined velocity while compensating for the torque and shear generated from both the material becoming extruded and the screws used. However, regardless of the size and kind of the screw in the stationary barrel a typical extrusion set up consists of a motor which acts as a drive product, an extrusion barrel, a rotating screw, and an extrusion die [13]. A central digital control unit is connected to the extrusion unit so that you can control the process parameters such as screw speed, temperature, and pressure [14] therefore. This electronic control unit acts as a monitoring product as well. The normal length diameter ratios (L/D) of screws positioned inside the stationary barrel will be another essential characteristic to consider whether the extrusion tools is a single-screw or twin-screw extruder. The L/D of the screw either in a single-screw extruder or a twin-screw extruder commonly ranges from 20 to 40?:?1 (mm). In the event of the use of pilot plant extruders the diameters of the screws considerably ranges from 18 to 30?mm. In pharmaceutical scale up, the production machines are much larger with diameters commonly exceeding 50-60?mm [15]. Furthermore, the measurements of a screw switch over the foam extrusion manufacturer amount of the barrel. In the most advanced processing products for extrusion, the screws could be separated by clamps or be extended compared to the length of the barrel itself. A basic single-screw extruder consists of three discrete zones: feed zone, compression, and a metering zone (Figure 2). Under the compression zone that is basically referred to as processing zone could be associated with few other procedures such as mixing, kneading, and venting [13, 15].

Amount 2: Schematic diagram of a single-screw extruder [10].

The depth together with the pitch of the screw flights (both perpendicular and axial) differ within each area, generating dissimilar pressures along the screw length (Figure 3). Normally the pressure within the feed area is quite low in buy to allow for regular feeding from the hopper and gentle blending of API, polymers, and various other excipients and therefore the screw trip depth and pitch happen to be kept bigger than that of various other zones. At this stage of the process the pressure within the extruder is quite low which subsequently gets improved in the compression area. This process results in a gradual upsurge in pressure along the amount of the compression zone, which efficiently imparts a high amount of combining and compression to the material (by reducing the screw pitch and/or the trip depth) [9, 15]. Moreover the major goal of the compression area isn't just to homogenize but likewise compress the extrudate to guarantee the molten material reaches the final section of the barrel (metering area) in an application befitting processing. Finally the final section which is known as the metering area stabilizes the effervescent move of the matrix and ensures the extruded product includes a uniform thickness, condition, and size. A constant and continuous uniform screw airline flight depth and pitch helps to maintain constant high pressure ensuring a uniform delivery price of extrudates through the extrusion die and hence a uniform extruded item.

Amount 3: Screw geometry (extrusion) [9].

In addition to the above-mentioned systems, downstream auxiliary tools for cooling, cutting, and collecting the finished item can be typically employed. Mass flow feeders to accurately meter materials into the feed hopper, pelletizers, spheronizer, roller/calendaring device so as to produce continuous movies, and process analytical technology such as for example near infrared (NIR) and Raman, ultrasound, and DSC systems are options also. Throughout the whole process, the temperature in every zones is controlled by electrical heating bands and monitored by thermocouples normally.

The single-screw extrusion system is easy and offers lots of advantages but even now does not acquire the combining capability of a twin-screw equipment and for that reason is not the preferred approach for the production of all pharmaceutical formulations. In addition, a twin-screw extruder gives much greater versatility (process manipulation and optimisation) in accommodating a wider range of pharmaceutical formulations causeing this to be setup much more constructive. The rotation of the screws in the extruder barrel may either come to be corotating (same course) or counter-rotating (opposite direction), both directions being equivalent from a processing perspective (Figure 4). A greater degree of conveying and far shorter residence times will be achievable with an intermeshing set up. Furthermore, using reverse-conveying and forward-conveying components, kneading blocks, and other intricate models as a means of improving or controlling the level of mixing required might help the construction of the screws themselves to end up being varied [16].

Figure 4: A good twin-screw extruder and screws [9].

4. Disadvantages and benefits of HME

HME offers several advantages over conventionally obtainable pharmaceutical processing approaches including (a good) increased solubility and bioavailability of water insoluble substances; (b) solvent-free nonambient process; (c) economical process with reduced production period, fewer processing measures, and a continuous operation; (d) functions of sustained, altered, and targeted release; (e) better content material uniformity in extrudates; (f) no requirements for the compressibility of substances; (g) uniform dispersion of great particles; (h) good stability at changing pH and wetness levels and safe request in human beings; (i) reduced number of unit operations and production of an array of performance dosage forms (j) a variety of screw geometries [17-21].

However, HME has plenty of disadvantages as well. The primary drawbacks of HME contain thermal process (drug/polymer stability), use of a limited amount of polymers, high stream properties of polymers, and excipients required and not suitable for relatively high temperature sensitive molecules such as for example microbial species and proteins

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