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Hot melt extrusion and injection molding technology
Definitions
Hot melt extrusion (HME) has been used in many diverse industrial fields, mostly with the processing of foods and the manufacturing of plastics. The first industrial use of single-screw extruders was in the mid-nineteenth century with the extrusion of thermoplastic materials. Since then, it became a very interesting technique used in the pharmaceutical industry with proven robustness for numerous drug delivery systems (DDS) [26,27]. Hot melt extrusion related patents, which have been issued for pharmaceutical systems have steadily increased since the early 1980’s.
So far, the U.S.A and Germany are the leading of issued patents for hot melt extrusion in the market [28].
Hot melt extrusion is a continuous process in which material melts or softens under elevated temperatures and is further forced through a die, usually with the help of one or two conveyer screws in a barrel. During the process, the material is exposed to heating and intense shear allowing a homogeneous distribution of drug particles in a molten carrier [29].
The marked hot melt extruders have either one screw or two screws. The latter leads to better mixing of the drug and polymer. Two screws are disposed side-by-side, allowing for different configurations in all zones from the start of the product mixing to the output of the dosage form. Moreover, the screws are either rotated in the same (co-rotating) or in the opposite direction (counter rotating). The latter option is able to blend drug and polymer even in case of high viscosity, which required high shear forces. Furthermore, the friction between the barrel, blending, and rotating screws provides the driving force for the material in order to reach the die. It is to emphasize that depending on the marked hot melt extruder, the material can be fed at different locations, which can be very practically beneficial in case of the addition of additives during the process. Importantly, liquids can also be introduced using a liquid pump and liquid injection system [29]. Due to increased barrel temperature, the materials melts or fuses after it enters into the transition zone. The drug is embedded homogenously within the carrier (polymer) with help of screws and the mixture moves along the barrel towards the die. When the material reaches the output, it is delivered through the die cavity and sized to obtain its final shape (figure 4) [30].
The adjustment of extrusion parameters is of utmost importance in the manufacturing of such polymeric drug delivery systems. Adjustable parameters include screw speed, processing temperature and feeding rate, which impact the shear stress (torque) and mean residence time and in the long term also dissolution rate and stability of the final product [29]. In this purpose, extruder sensors are able to measure the barrel and die temperatures, the torque generated, the melt pressure, the feed rate, the screw speed and the melt temperature during the process. Moreover, other thermos analytical techniques such as hot-stage microscopy, differential scanning calorimetry, micro calorimetry, X-ray diffraction (XRD), dynamic mechanical thermal analysis (DMTA) and thermogravimetric analysis (TGA) are often applied to investigate the chemical stability, thermal behavior and crystalline properties of actives: and/or excipients in the final dosage form [31].
Pharmaceutical applications of hot melt extrusion
Hot melt extrusion is a continuous and free solvent process allowing for the preparation of solid dispersions or solutions, depending on drug solubility in the matrix former (often a polymer) as well as drug concentration in the system. Such solid dosage forms have the potential to improve drug bioavailability, efficacy and safety of the drug treatment. Hot melt extrusion is used to produce different polymeric drug delivery systems administrated via oral route such as polymeric films [32,33] and tablets [34-36] but also transdermal [37], transmucosal [38,39] and intra ocular (implants) route [40,41]. The production of three types of solid dispersions are described: (i) an amorphous solid dispersion where both the drug and the carrier are amorphous but the drug is dispersed in a particular form within the polymer (DSC thermogramm shows two Tg corresponding to those of drug and polymer) (ii) a crystalline solid dispersion, where all/a fraction of the drug remains crystalline in an amorphous polymer (DSC thermogramm shows a Tg corresponding to the polymer and a fusion/dissolution pic corresponding to the drug) and (iii) an amorphous solid solution where both the drug and the carrier are amorphous and completely miscible, which can be indicated by one Tg in the DSC thermogramm. Note that the drug is dispersed at the molecular level in case of an amorphous solid solution [42]. An amorphous solution have the advantage to increase drug availability by improving its solubility. In a crystalline suspension, the drug crystals are dispersed in the amorphous matrix which is suitable for a controlled drug delivery. Amorphous solid suspension are the less stable with a high tendency to recrystallization. Indeed, the drug is in an amorphous state and is dispersed in the formulation. The type of the solid dispersion obtained depends on the drug solubility in the polymer, the stability of the final form and the drug – polymer interactions [43].
The choice of the polymer nature is critical in the formulation process and its application. Some of the most well-known applications of hot melt extrusion are:
Taste masking of drugs [44-47].
Solubility enhancement of poorly water-soluble compounds for an immediate drug release [48-51].
Sustained and time controlled release [52-55], and extended drug delivery systems [56]. Site specific drug delivery systems [57-59].
In addition to these current applications, some recent innovations have to be mentioned, such as co-extrusion [60-62], co-crystallization [63-66], 3D printing [67-69] and injection molding [70-73].
Materials used for hot melt extrusion
Drugs
The properties of the active drug substance often limit the formulation and processing choices available to the pharmaceutical scientist in the development of dosage forms. Hot melt extrusion is a free solvent process, which avoids potential hydrolytic degradation pathways. In addition, poorly compactable materials can be prepared as tablets without a compression process by cutting an extruded rod to the desired dimensions. Furthermore, depending on the materials used, hot melt extrusion can be useful to enhance the bioavailability of poorly soluble drugs. It can also protect a drug from enzymatic degradation as well as avoid the irritation of the mucosa in gastro intestinal tract. Moreover, if the drug has a specific absorption window or need to be targeted at a specific area of the gastro intestinal tract for systemic or localized treatment of diseases (e.g. Crohn’s disease and Ulcerative Colitis), hot melt extrusion can be used.
Prior to the hot melt extrusion process, deep knowledge of the physicochemical properties of the drug as well as the polymer used is essential for the feasibility of the extrusion process. It is to emphasize that physicochemical characterization of the drug is extremely important for the development of drug delivery systems (e.g. solubility, physical state, particle size, flowability, melting/glass transition temperature and thermal degradation) [74].
Carriers
In hot melt extruded drug delivery systems, the active compound is embedded in a carrier formulation often comprised of one or more “meltable” substances and other functional excipients. The meltable substance is generally a polymer (natural or synthetic) or a lipid. The selection of the carrier material for pharmaceutical drug delivery systems strongly depends on the application (taste masking, immediate or sustained release). The choice of the pharmaceutically approved polymer is critical in the formulation process as its properties not only dictate the processing conditions but also govern the dissolution characteristics of the dosage form (drug release kinetics and release mechanism).
As for drugs, some relevant characteristics of the carrier should be well investigated proceed to hot melt extrusion [31]. Here there are mostly important factors: the chemical structure, the solubility, the glass transition temperature/melting temperature, the melt viscosity that can be improved by the addition of plasticizer, the flowability, the lipophilicity/hydrophylicity, the thermal stability, the drug-carrier interactions and compatibility. Moreover, the characterization of rheological properties can help in selecting the appropriate carriers and setting the process conditions, which can be cost and time consuming [74].
Some of the carriers used for hot melt extrusion and their appropriate studies are listed below:
Ethylene vinyl acetate (EVA): a water-insoluble copolymer of ethylene and vinyl acetate (VA). By simple varying the ethylene/VA ratio, large spectrum of drug release profiles can be provided [75-77].
Poly-vinyl acetate (PVAc): a water insoluble polymer, which is suitable for hot melt extrusion [78,79].
Cellulose derivatives: Hydroxy Propyl Methyl Cellulose (HPMC) is a non-ionic water soluble polymer, which is widely used for the preparation of controlled release tablets, microparticles and films by HME [80-83]. Hydroxypropyl cellulose (HPC) is also a non-ionic water-soluble and pH insensitive cellulose ether, which has been successfully used as matrix former and solubility-enhancing agent [84,85]. Ethyl Cellulose (EC) is a non-ionic water insoluble polymer [86,87].
Copolymers derived from esters of acrylic and methacrylic acid have various physicochemical properties due to the nature of their functional groups. Commercially available “Eudragit ®” for immediate release (E100, E PO), delayed release (S100, L100) or sustained release (NE, NM, RL, RS) [88-97].
Poly Ethylene Oxides (PEO) have the same composition as Poly Ethylene Glycol (PEG) but can be obtained at much higher molecular weights (100 KDa to 7000 KDa), they can be used in controlled drug delivery systems [42,98-100] as well as plasticizers [101-103] depending on their molecular weight.
Polyurethane are produced by a reaction between polyols (polyethers or polyesters) and diisocyanates. They are copolymers containing soft and hard segments through which they have thermoplastic and elastic properties. Polyurethanes have been used as carriers for hot melt extrusion for the preparation of vaginal rings [104,105] and tablets for oral controlled drug delivery [106,107].
Biopolymers (e.g. polysaccharides) such as chitosan (animal origin) and xanthan gum have been used as matrix in hot melt extrusion for oral sustained release formulation [108,109].
Plasticizers and additives
The addition of plasticizers can lower the processing extrusion temperatures that can avoid heat degradation of drugs and carriers [110-112]. A plasticizer is a low molecular weight compound that softens the polymer to make it more flexible, decreases the glass transition temperature (Tg) and lowers the melt viscosity [113-115]. The plasticizer can increase the free volume between polymer chains, providing more mobility for the polymer chains, which results softer and more flexible mixture. Being more flexible, the processing temperature can be decreased, which leads to lower torque generated during the process [116,117]. Furthermore, the physical and mechanical properties of the final product can be improved. Most common plasticizers used are low molecular weight polyethylene glycols, triacetin, triethyl citrate, glycerol, dibutyl sebacate…etc. Moreover, several drugs (e.g. ibuprofen, guaifenesin, metoprolol tartrate) have been shown to be effective plasticizers for certain polymers [118-120]. Since the drug and polymer are exposed to elevated temperatures, high pressure and extensive mixing during hot-melt extrusion, it is important to evaluate the stability of the API and polymer after the manufacturing process in order to avoid degradation. In order to be efficient, several prerequisites have to be fulfilled by plasticizers, namely good efficiency, polymer-plasticizer compatibility/affinity and thermostability. The efficiency of a plasticizer refers to the concentration of plasticizer necessary to lower the glass transition temperature of the polymer. Compatibility refers to the similarity in chemical structure between plasticizer and polymer, which results in a better compatibility. The nature of the plasticizer can have an impact on drug release kinetics: a hydrophobic plasticizer could be remained into the polymeric network, retarding the release of a drug into the bulk media but in contrast the leaching out of the hydrophilic plasticizer from the polymeric network can be rapid, which can creat more pores into the system and thus, accelerating drug release [121,122].
Table of contents :
I. INTRODUCTION
1. General
2. Oral controlled drug delivery
3. Hot melt extrusion and injection molding technology
4. Colon targeting
5. Purposes of this work
II. MATERIALS AND METHODS
1. Materials
2. Preparation of dosage forms
3. Physicochemical characterizations
III. RESULTS AND DISCUSSIONS
CHAPTER 1: POLYVINYL ACETATE:POLYSACCHARIDE BLENDS FOR COLON TARGETING
1. Effect of polysaccharide nature and amount in thin polymeric films
2. Effect of polysaccharide nature on pH level
3. Impact of hydrophobic polymer nature in thin polymeric films
4. Effect of the amount of polysaccharide in hot melt extrudates
5. Impact of drug loading in hot melt extrudates
CHAPTER 2: POLYURETHANE:POLYSACCHARIDE BLENDS FOR COLON TARGETING
1. Influence of polyurethane nature in hot melt extrudates
2. Effect of polysaccharide and plasticizer nature in hot melt extrudates
3. Impact of polymer:polymer blend ratio in hot melt extrudates
4. Influence of polymer:polymer blend ratio in injection-molded capsules
CHAPTER 3: HOT MELT EXTRUDED POLYSACCHARIDE BLENDS FOR CONTROLLED DRUG DELIVERY
1. Impact of the type of polymer blend & plasticizer addition
2. Ethylcellulose:guar gum blends
IV. CONCLUSIONS AND PERSPECTIVES
V. RESUME IN DETAIL (FRENCH)
VI. REFERENCES
VII. PUBLICATIONS AND PRESENTATIONS
