Application of ultrasound-assisted compression in pharmaceutical technology. Design and optimization of oral sustained-release dosage forms

1 APPLICATION OF ULTRASOUND-ASSISTED COMPRESSION IN PHARMACEUTICAL TECHNOLOGY. DESIGN AND OPTIMIZATION OF ORAL SUSTAINED-RELEASE DOSAGE FORMS M. Millán-Jiménez, E. Galdón, C. Ferrero*, I. Caraballo Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Universidad de Sevilla, Seville, Spain. *Corresponding author: Carmen Ferrero Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Universidad de Sevilla.C/ Prof. García González nº 2, 41002 Seville, Spain. Tel.: + 34 954 557218. E-mail: [email protected] 2 Abstract Ultrasound-assisted compression (USAC) is a technology combining a conventional compression process and US irradiation. These mechanical and thermal effects lead to heating, melting and sintering of materials. This article reviews the principles of ultrasound-assisted compression and its main applications in pharmaceutical technology. Physical properties of the materials and process parameters such as time, energy and inter-punch distances should be carefully controlled to guarantee reproducibility and a complete transition of the material. The application of ultrasounds during compression improves the mechanical strength of tablets, a clear advantage for formulations with high-doses of poor compressible drugs. Ultrasounds have also demonstrated its usefulness as a technique to prepare solid dispersions, enhancing the bioavailability of poorly soluble drugs. The formulation of sustained-release oral dosage forms has also benefit from the application of USAC, as a better control of drug release with a minor quantity of excipient could be obtained. The continuum percolation model provides a physical basis to explain the important decrease in the excipient percolation threshold using this technology. This model together with the quantification of the Excipient Efficiency parameter, are valuable tools to understand the drug release properties from sustainedrelease systems. Keywords: Ultrasound-assisted compression; Tableting; Solid dispersion; Controlled release; Percolation threshold; Excipient Efficiency 3 1. Introduction Hot-processing techniques (hot-melt extrusion -HME-, injection-molding -IM-, threedimensional printing by fused deposition modelling -FDM-, ultrasound-assisted compression- USAC-) have emerged as new processing technologies for the development of solid dosage forms and they are showing promising results in manufacture of immediate and controlled release systems. Ultrasound (US) energy has been used for several years in metallurgy, plastics and ceramics industries for joining dissimilar materials such as metals and polymers [1,2]. The automotive industry has used it regularly since the 1980s. Recent applications in the food field includes fine-particle removal from emulsions, agglomeration and defoaming [3]. The first applications of ultrasounds to the pharmaceutical field date from two patents in 1993 and 1994 [4,5]. Gueret [4] used powder mixtures containing from 5 to 80% w/w of at least one thermoplastic material, such as polyethylene, polystyrene, polyamides, polyvinyl chloride and poly(ethylene terephthalate). The remainder composed of at least one non-thermoplastic mineral or organic substance. It was found that the presence of a thermoplastic polymer in the formulation allowed the formation of a framework that held the non-thermoplastic powders together. Motta [5] used powder mixtures of an active ingredient from 30 to 75% w/w and suitable excipients in the range from 70 to 25% w/w to obtain pharmaceutical forms applying ultrasound and mechanical compression (avoiding granulation or extrusion). The active ingredient could be released in a delayed or rapid but controlled manner based upon the choice of the excipients. Since then, different papers [6–11] have dealt with the application of ultrasounds in pharmaceutical technology: compression of active pharmaceutical ingredients, formulation of solid dispersions to enhance the bioavailability of poorly soluble drugs and formulation of sustained release dosage forms. Nevertheless, this technique has not been widely used despite the promising results obtained. The complex phenomena involved in the process as well as the absence of a clear knowledge of the effect of the application of US energy on the final properties of the dosage form could be some of the reasons of its limited use. The objective of this study was to review the literature concerning the application of ultrasound-assisted compression in pharmaceutical technology. Attention will be focused on the possibilities offered by this technique in the formulation of sustained release dosage forms. Moreover, the paper deals with the usefulness of the percolation theory to predict the technological and biopharmaceutical properties of matrix systems developed by USAC. This 4 model, together with the quantification of the Excipient Efficiency parameter, could serve as valuable tools for optimizing the design of formulations by this technique. 2. Principles of ultrasound-assisted compression technique (USAC) Ultrasound energy refers to mechanical waves above the audible frequencies; normally frequency waves equal or higher than 20 kHz. Ultrasonic waves are of the same nature as sound waves and their propagation and absorption in various media are governed by the laws that apply to sound transmission. Even in the presence of obstacles, they are able to travel along different materials [12]. As a wave propagates through a medium, its amplitude decreases or attenuates. There are several causes of this attenuation, such as spreading of the wave front, conversion of the acoustical energy to heat and scattering from irregular surfaces [12]. The rate of propagation depends upon the type of wave, the elastic properties of the medium, the density of the medium, and, in some cases, the frequency and amplitude. The propagation speed of ultrasounds in a specific medium may be lower or higher than in vacuum. Ultrasonic applications can be classified as being either low or high intensity. At low intensities, ultrasound is used to investigate structural properties of materials including living tissues [13]. In this case, the material under study does not suffer any permanent change in its structural and chemical properties. At high intensities, ultrasound is generally used for changing the properties of the material, being the changes often permanent. In terms of pharmaceutical powder compression, high-intensity ultrasound is used [14]. High-power ultrasound presents, in general, nonlinear interactions. Such interactions may involve shock waves and harmonic generation (inducing cavitation phenomena) and a wide range of other phenomena that are thermal, mechanical and chemical in nature [12,14]: Thermal effects: As ultrasound progresses through a medium, energy is lost in the form of heat mainly due to reflections. The amplitude of ultrasonic vibration is directly proportional to the amount of energy converted to heat. Mechanical effects: Ultrasound produces agitation and random motion of the particles in the material, inducing its compaction. Stresses developed in an ultrasonic field can cause ruptures in the materials and severe erosion of their surfaces. Chemical effects: The primary mechanisms of enhanced chemical reactions under the influence of high-intensity ultrasound are cavitation and intimate mixing of reactive and catalytic components. Nevertheless some chemically related effects of ultrasonic energy are due to absorption of heat, especially oxidation reactions. Ultrasound has 5 been reported to promote polymerisation or de-polymerisation depending upon the nature of the molecules being treated. Thermal and mechanical effects are involved in the production of tablets by ultrasoundassisted compression. Besides these effects on solids, US also acts on liquids or melt mixtures, causing cavitation and an extreme molecular motion that divide a drop of liquid material into a number of microdrops with a very narrow range of sizes. This physical principle could be employed to prepare multiparticulate drug delivery systems [8]. Ultrasound-assisted compression equipment contains the following basic components: US generator: An electrical high-frequency unit, which converts conventional 50 to 60 Hz electrical input into a high frequency alternating electrical output in the ultrasonic range of 20 to 50 kHz. In the pharmaceutical field 20 kHz is used. Outputs may vary from 50 watts to several kilowatts as required. Transducer: Converts the high-frequency electrical output of the generator into highfrequency mechanical vibrations. Usually piezoelectric transducers are used (mainly made with special ceramic materials). Acoustic coupler (sonotrode): Focuses, amplifies and transmits the mechanical vibrations from the transducer to the powder in the die. Time, energy and amplitude of the US-waves are carefully controlled in order to achieve the transition of the material and manufacture the tablets. Time from 4 to 10 seconds, energy from 400 to 1400 Joules and inter-punch distances below 7 mm are currently used. Distances larger than 7 mm lead to high variability of results and poor transitions of the material. Although the use of ultrasounds increases the compaction time compared with conventional direct compression, the enhanced compactibility and more homogeneous distribution between drug and excipient [15,16] obtained by USAC could overcome this drawback. Moreover, this technique reduces the quantity of material and the production time compared with contemporary hot-processing techniques such as HME [10]. Fig. 1 shows the process of the manufacture of a tablet by means of ultrasound-assisted compression. In the initial state (Fig. 1a) sample is poured into the die covered at the top and bottom by tetrafluoroethylene (Teflon®) sheets. Pressure is applied with the lower punch to achieve a precompaction of the sample (Fig. 1b) ensuring a good transmission of ultrasound energy from sonotrode to the material. Ultrasound is applied by the upper punch-sonotrode (Fig. 1c) and the movement of the powder particles increases, increasing their packaging and the friction and collisions between them. As a consequence, the temperature rises producing a glass transition to the rubbery state of those components with thermoplastic properties. This stage lasts until a preset parameter (the sonication energy, the sonication time or the final 6 position of the lower punch) is reached. After a cooling stage (Fig. 1d), a period to reestablish the new solid properties of the sample, the tablet is ejected (Fig. 1e). It is important to emphasize the need to use a Teflon® sheet to protect the sonotrode and the lower punch. It also serves as thermal insulator. Under well-controlled working conditions, contamination of the tablets with Teflon is unlikely, as its melting point is higher than 300 °C. 7 Fig. 1. Ultrasound-assisted compression process. (a) Initial stage, (b) Precompaction, (c) Compaction assisted with ultrasound irradiation, (d) Cooling stage and (e) Ejection of tablet. In summary, in the process of ultrasonic compression, the porosity of the powder material is reduced by a conventional compaction process and the US irradiation from a generator coupled to the upper punch causes powder friction, leading to heating and sintering of materials. Aspects such as material suitability and/or drug stability should be taken into account when applying ultrasound-assisted compression. Physical properties of the materials such as melting point, ability to undergo plastic deformation, particle size and particle shape might affect the results of this technique [17]. The particle size and shape affect the transmission of the compaction force and the characteristics of the resulting tablet [10]. The amount of material used for manufacture of the tablets is then limited by its bulk density. As USAC process involves a form of thermal fusion, it was best suited to those materials with a high modulus of elasticity and a low melting point. In addition to the melting point, the glass transition temperature (Tg) of the polymer is a crucial factor in the heating process as the physical change of the polymer during the ultrasound compaction is predominantly affected by this parameter. The required US energy for a complete transition of the polymer increases with Tg [10]. When the thermoplastic polymer is subjected to temperatures higher than the Tg, mechanical pressure and frictional forces, the sintering of the particles can be produced causing the boundaries between them to be indistinguishable. In this way the excipient surrounds the pharmaceutical active ingredient more efficiently. However, the temperature increase caused by ultrasounds within the powder bed might also lead to unwanted changes in physical or chemical characteristics of the drug [17]. Properly controlled process conditions should be established to avoid drug degradation. Several authors [16,18] have reported no degradation of the drug using different analytical techniques. A good understanding of the relationship between the US compaction parameters and the material properties is thus necessary to guarantee the quality of the US-compacted product. 3. Application of ultrasounds in pharmaceutical powder compression The preferred method of tablet manufacture is direct compression, for reasons such as simplicity, fast processing, lower costs and increased stability of drugs. However, direct 8 compression of a highly dosed drug, such as paracetamol, which has poor compressibility and flow properties, is not possible. On the other hand, the compression of a powder is a complex process that is usually affected by different kinds of problems. These problems have been widely investigated and mainly concern the volume reduction and the development of strength between the particles of the powder, sufficient to keep the tablet integrity [19]. The application of ultrasound energy has shown a great ability to reduce and even avoid these problems. Poor compactibility of pharmaceutical powders is one of the main causes of tablet defects such as friability, sticking, capping, lamination... Ultrasounds improve the characteristics of the compression process leading to optimized mechanical strength of the compacts at lower pressures as compared to conventional tableting. Ultrasounds cause a temperature rise within the tablet that increases the extent of plasticity and interparticle bonding, resulting in stronger and less porous tablets [15,17]. Levina and Rubinstein [9] prepared coherent ibuprofen tablets by ultrasound-assisted compression at pressures as low as 20-30 MPa. The breaking forces of these tablets were found to be significantly higher than the obtained for conventional compaction. The crushing strength of the tablets significantly increased as the duration of the ultrasounds application increased. The application of ultrasounds during compaction favours particle rearrangement in the powder bed, leading to an increase in the apparent density, a larger area of contact and consequently, a higher degree of bonding. In addition, melting at the interparticle contact points results in strong solid bridges between particles. Thus, tablets exhibit less elastic recovery and are less likely to cap. Moreover, the trapped air in the powder can escape more readily during ultrasonic vibration [17,20]. 4. Application of ultrasounds in preparation of solid dispersions The development of poorly soluble drugs has increased in the last decades, leading to the need of formulations that enhance their solubility and, therefore, their absorption. Among solubility enhancement technologies, solid dispersion is one of the most useful and could be obtained by solvent, melting and/or mechanical methods. Ultrasound-assisted compression technique has been evaluated as an alternative method for bioavailability enhancement of poorly soluble drugs by means of a direct processing of the powder mixture, in the absence of organic solvents or evaporating apparatus [15]. 9 Sancin et al. [21] reported the amorphisation of ketoprofen, a poorly water-soluble drug, by US compaction treatment. The drug appeared as a soft and dense paste (due to melting at 96 oC) and the crystallinity was recovered after few hours from the US treatment. Binary mixtures of ketoprofen with Eudragit® S100, a thermoplastic acrylic polymer soluble at pH > 7, were also compacted by USAC. DSC studies revealed a decrease in crystallinity of ketoprofen depending on the excipient/drug ratio and the US energy supplied. The presence of Eudragit® slowed down or prevented the regeneration of the drug crystallinity as the molten phase adsorbed on the surface of the excipient particles maintaining the drug in this glassy state. The authors conclude that this association could be interesting in the preparation of pH controlled dosage forms that release the drug in the physiological medium of the intestine. A further demonstration of important physical modifications of solids compacted under US was reported by Fini et al. [8]. US-discharge during compaction reduced the crystallinity of both drug and excipient in solid dispersions containing indomethacin (a poorly water-soluble drug) and low melting excipients such as polyethyleneglycols (PEGs) of different molecular weights. Indomethacin was partially dissolved in the excipient causing an increase of the dissolution rate of the drug. The extent of a back-crystallisation, which reduces the dissolution rate, as a function of the ageing of the material, depends on the type of the selected PEG. As a continuation of this research, physical mixtures of indomethacin with lactose-based excipients (Ludipress® and Cellactose®) were compacted with the aid of ultrasounds [22] to prepare a new generation of granules by milling of US-compacted matrices. Important modifications were observed on indomethacin physical state, being the drug spread on the excipient particle surface as a thin film, giving a lustrous appearance. No influence of ultrasounds was observed on phase transition concerning lactose. Dissolution profiles suggested an increased release of the drug from the systems treated with ultrasounds with respect to a traditional compaction. Kalidova et al. [18] examined also the feasibility of US-assisted compression technique in preparation of solid dispersions using fenofibrate (a poorly water-soluble drug) and various polymers (Eudragit® EPO, Kollidon® VA 64, Soluplus®, HPMC 2910/5, Povacoat® MP) as carriers. The ultrasound energy was not sufficient enough to cause a complete amorphisation of the crystalline drug substance. An enhancement in dissolution behavior was achieved compared to the untreated physical mixture of drug and excipient but the dissolution profiles were similar to those obtained by adding the polymeric carrier directly to the dissolution medium. Moreover, the authors addressed the importance of monitoring the US compaction 16 Elsevier, Cambridge, UK, 2015, pp. 295–312. 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Fig. 2. Influence of KCl dose on drug release profiles from traditional tablets (Trad) and ultrasound tablets (US). Fig. 3. SEM micrograph showing the cross section of US tablets with 50%w/w drug content KCl (white particles) is surrounded by the excipient (shadow). Fig.4. Drug release profiles of traditional tablets (Trad) and ultrasound tablets (US) containing 50%(w/w) KCl and 50%(w/w) Eudragit® RSPM. The excipient particle size (100-150 μm) was kept constant and the drug particle size was different. 0 50 100 150 200 250 300 0 20 40 60 80 100 Trad 30% KCl Trad 50% KCl Trad 70% KCl US 30% KCl US 50% KCl US 70% KCl Time (min) % KCl released 0 50 100 150 200 250 300 0 20 40 60 80 100 Trad 100-150 µm KCl Trad 200-250 µm KCl US 100-150 µm KCl US 200-250 µm KCl Time (min) % KCl released