Use of Spherical Techniques in Pharmaceuticals by Rohan Satwara

Use of Spherical Techniques: 

Use of Spherical Techniques Presented by : Rohan Satwara M.Pharm S-III Guided by : Mrs.Meenakshi Patel Place : Babaria Institute Of Pharmacy Varnama ,Vadodara 1 Satwara Rohan

Content: 

Content What is it…and why Novel spherical techniques Conventional spherical techniques GTU questions References 2 Satwara Rohan

Spherical techniques and Advantages: 

Spherical techniques and Advantages Spherical techniques convert fine powder blend of drug(s) or Excipients or both into small, free flowing, spherical units referred as pellets that possess properties suitable for their ease of manufacturing and also improved rheological and physicochemical properties. Main advantages associated with spherical particles : Optimum flow and handing characteristics : The flow characteristics of spheres make them suitable for most system suitable for pharmaceutical industries. More reproducible packing Into small containers : The packing of small spheres into small containers like capsules or larger packages is much more convenient than other dry forms such as powder or granules. 3 Satwara Rohan

Conti..: 

Conti.. Minimum surface/volume ratio : spheres provide lowest S/V ratio and thus pharmaceutical compounds can be coated with a minimum of coating material. Important for effective release of some drugs. Optimum shape for coating and controlled release : spheres are dense material having smooth surfaces that can be effectively coated than any other shape thus providing controlled release of drug. Easy mixing of non compatible products : spherical particles are easily mixed so avoiding drug incompatibility problems. Spheres are providing more therapeutic qualities of dosage form due to more dose accuracy and handling properties 7) Spheres offering large surface area and they get least affected by the normal gastric emptying time and hence drug delivery system is less affected by physicochemical changes. 4 Satwara Rohan

Various techniques : 

Various techniques Novel techniques : Spherical crystallization Crystallo-co-agglomeration Extrusion spheronization Hot melt extrusion Sonocrysatallization /melt Sonocrysatallization , SAXS Pastillation Conventional techniques : Wet granulation Fluidized bed dryer Spray drying / spray congealing Powder layering 5 Satwara Rohan

Spherical crystallization: 

Spherical crystallization In 1986, Kawashima et al used the spherical crystallization technique for size enlargement of the drug in the field of pharmacy. Spherical crystallization is a particle design technique, by which crystallization and agglomeration can be carried out simultaneously in one step and which has been successfully utilized for improvement of flow ability, compact ability and bioavailability of crystalline drugs. 6 Satwara Rohan

Need of spherical crystallization: 

Need of spherical crystallization Mechanical micronization of crystalline drugs and incorporation of surfactants during the crystallization process are the techniques commonly used to improve the bioavailability of poorly soluble drugs. The mirconization process alters the flow and compressibility of crystalline powders and cause formulation problems. Addition of surfactant generally led to less significant increase in aqueous solubility. To overcome this problem Kawashima developed a spherical crystallization technique. 7 Satwara Rohan

Advantages : 

Advantages Spherical crystallization technique has been successfully utilized for improving of flowability and compressibility of drug powder. This technique could enable subsequent processes such as separation, filtration, drying etc to be carried out more efficiently. By using this technique, physicochemical properties pharmaceutical crystals are dramatically improved for pharmaceutical process i.e. milling, mixing and tabletting because of their excellent flowability and packability. This technique may enable crystalline forms of a drug to be converted into different polymorphic form having better bioavailability. For masking of the bitter taste of drug. Preparation of microsponge, microspheres and nanospheres, microballoons, nanoparticles and micro pellets as novel particulate drug delivery system. 8 Satwara Rohan

Mainly four techniques are used : 

Mainly four techniques are used Wet spherical agglomeration method (WSA) Quasi emulsion solvent diffusion method Ammonia diffusion method Neutralization method 9 Satwara Rohan

Wet spherical agglomeration(WSA)technique: 

Wet spherical agglomeration(WSA)technique Here the good and the poor solvents are freely miscible and interaction (binding force) between the solvents is stronger than drug interaction with the good solvent, which leads to precipitation of crystals immediately . Bridging liquid collects the crystals suspended in the system by forming liquid bridges between the crystals due to capillary negative pressure and interfacial tension between the interface of solid and liquid. WSA method proceeds in three steps as shown in Fig. precipitate crystals from saturated solution of drug, i.e., thermal method (temperature decrease or evaporation), physicochemical methods (addition of another solvent, salting out) and chemical reaction. The second step is the choice of the wetting agent or bridging agent that will be immiscible with the poor solvent of crystallization. It will act to adhere crystals each other. Finally, the third step is the hardening of the agglomerates. 10 Satwara Rohan

Slide 11: 

11 Satwara Rohan

Quasi emulsion solvent diffusion method : 

Quasi emulsion solvent diffusion method here interaction between the drug and the good solvent is stronger than that of the good and poor solvents; hence the good solvent drug solution is dispersed in the poor solvent, producing quasi emulsion droplets, even if the solvents are normally miscible. This is because of an increase in the interfacial tension between good and poor solvent . Then good solvent diffuses gradually out of the emulsion droplet into the outer poor solvent phase. The counter diffusion of the poor solvent into the droplet induces the crystallization of the drug within the droplet due to the decreasing solubility of the drug in the droplet containing the poor solvent. This leads to precipitation of drug crystal agglomerates. This method is used to prepare microspheres. 12 Satwara Rohan

Slide 13: 

13 Satwara Rohan

Ammonia diffusion method : 

Ammonia diffusion method In this technique, ammonia-water system is used as the good solvent and bad solvent is selected depending upon the drugs solubility in that solvent which is usually acetone. The ammonia-water also acts as a bridging liquid as well as good solvent . This technique usually meant for Amphoteric drugs which cannot be agglomerated by conventional procedures . The whole process is completed in three stages : First, the drug dissolved in ammonia water is precipitated. (Figure I). Simultaneously, ammonia in the agglomerate diffuses to the outer organic solvent i.e.acetone (Figure II). Its ability to act as a bridging liquid weakens and subsequently spherical agglomerates are formed ( FigureIII ). 14 Satwara Rohan

Slide 15: 

15 Satwara Rohan

Neutralization technique (NT) : 

Neutralization technique (NT) This technique involves the formation of fine crystals by neutralization and consequently their agglomeration by a bridging liquid. Spherical crystallization of Tolbutamide and Phenytoin were reported by this technique. The drug was dissolved in alkaline solution and then poured into an acidic solution containing polymers and bridging liquid under constant agitation. The drug crystals are precipitated out by neutralization of the base with acid. Then the precipitated crystals were simultaneously agglomerated with the incorporated polymer through the wetting action of the bridging liquid. 16 Satwara Rohan

Application of spherical crystallization: 

Application of spherical crystallization To improve the flowability and compressibility: For masking bitter taste of drug: For increasing solubility and dissolution rate of poorly soluble drug: 17 Satwara Rohan

Crystallo co agglomeration technique: 

Crystallo co agglomeration technique Spherical crystallization technique is restricted to only water insoluble large dose drugs only because several excipients such as disintegrating agent and diluents are hydrophilic in nature hence addition of these excipients in the agglomerates with help of organic bridging liquid is difficult. Due of this limitation, spherical crystallization can not be used to obtain agglomerates of low-dose or poorly compressible materials. To overcome this modification of the spherical crystallization technique was done and used for size enlargement of all, low dose, high dose, poorly compressible drugs and combination of drugs with or without diluents. In this technique drug is directly crystallized and agglomerated in combination with an excipient or with another drug with help of bridging liquid. Excipient or drug may or may not be crystallized in the system. This is known as Crystallo co agglomeration technique. 18 Satwara Rohan

Process steps of CCC: 

Process steps of CCC Homogenous mixture of drugs, diluents, polymers, disintegrant, surfactants are placed in Morishima vessel and wetted by solvent and bridging liquid with proper stirring to form homogenous mass. Walled baffles is then placed in Morishima vessel with aqueous solution of polymer in bad solvent with continuous stirring at constant speed for definite time period until spherical agglomerates is prepared. Endpoint of the process depends upon the size of agglomerates, clarity of supernatant and vaporization of solvent from the system. After completion of whole process, whole mass is decanted and washed with filtrate to prevent loss drug and polymer. Then agglomerates are dried in hot air oven for 24 hours to obtain dried agglomerates 19 Satwara Rohan

Application of CCC for improvement of tabletabilty: 

Application of CCC for improvement of tabletabilty 20 Satwara Rohan

Extrusion spheronization technique: 

Extrusion spheronization technique Extrusion-spheronization is a multiple-step compaction process comprising dry mixing of the ingredients with excipients, wet granulation o the mass, extrusion of the wetted mass, charging the extrudates into the spheroniser to produce a spherical shape, drying the wet pellets or spheroids in a dryer and, finally screening to achieve the required size distribution. 21 Satwara Rohan

Main steps involved : 

Main steps involved Dry mixing of drug + excipients Wet massing with binding agent Extrusion using different types of extruders Spheronization Drying in hot air oven screening 22 Satwara Rohan

Slide 23: 

AXIAL SCREW FEED EXTRUDER DOME SCREW FEED EXTRUDER RADIAL SCREW FEED EXTRUDER CYLINDER ROLL TYPE GEAR ROLL TYPE AXIAL PISTON EXTRUDER 23 Satwara Rohan

Mechanism of extrusion and spheronization : 

Mechanism of extrusion and spheronization 24 Satwara Rohan

Slide 25: 

Extrusion : The wet mass is forced through dies and shaped into small cylindrical particles with uniform diameter. Such shaping of the wet mass into long rods, commonly termed ‘ extrudate .’ The extrudate particles break at similar length under their own weight. Thus, the extrudate must have enough plasticity to deform but not so much that the extrudate particles adhere to other particles when rolled during spheronization process. Spheronization : A spheronizer also known as merumerizer consists of a static cylinder and a rotating friction plate where the extrudate is broken up into smaller cylinders with a length equal to their diameter and these plastic cylinders are rounded due to frictional forces. During spheronization process different stages can be distinguished depending upon the shape. The friction plate, a rotating disk with a characteristically grooved surface to increase the frictional forces, is the most important component of the equipment . 25 Satwara Rohan

Slide 26: 

Product features • Dust free • High spherocity • Free flowing • Compact structure • Low hygroscopicity • High bulk density • Low abrasion • Narrow particle size distribution • Smooth surface 26 Satwara Rohan

Hot melt extrusion: 

Hot melt extrusion Wet mass extrusion is the most frequently used method current a part from extrusion spheronization technique for producing spherical pellets, many drugs exhibit stability problems since granulating fluid employed in this process is generally water. In addition to this, pellets exhibit a rapid drug release and require a film coating to provide if controlled release properties are to be maintained. Researchers have investigated a new modified method for preparing matrix pellets for controlled release drug delivery system to overcome the disadvantages associated with wet mass extrusion and spheronization process which is called as a Hot Melt Extrusion (HME) method where a thermal agent softens or gets melted during the process to obtain matrix pellets. HME has been widely used technique in plastic industries and now it is used in pharmaceutical industries for formulation of sustained release, controlled release and transdermal as well as transmucosal drug delivery system 27 Satwara Rohan

Conti..: 

Conti.. Melt extrusion process consists of three basic steps: melting or plasticizing a solid material, Shaping the molten material and solidification of the material into the desired shape. A hot melt extrusion line consists of a material feed hopper, extruder inside a heated barrel, having three different sections, and spheroniser. The feed hopper holds the material and continuously feeds it into the extruder, which has a heated barrel containing the rotating screw. The extrudate is then cut into uniform cylindrical segments, which are spheronized to generate uniform sized pellets. The temperature maintained in the spheronizer should be high enough to soften the extrudate partially and facilitate its deformation and eventual spheroid formation. 28 Satwara Rohan

Equipment of melt extrusion: 

Equipment of melt extrusion 29 Satwara Rohan

Application of EST: 

Application of EST Verapamil hydrochloride floating pellets were prepared by spheronization process using microcrystalline PH 102, mannitol and kollidon CL. Evaluation studies carried out for it release and floating properties considering the effect of compression force suggest that Verapamil hydrochloride compressed tablet show slower release than the non compressed pellets. Dissolution performance of Eudragit L 100 and Eudragit S 100 based multi unit controlled release system formulated by extrusion spheronization using poorly soluble drug leukotrine antagonist Montelukast , when evaluated drug release occurred simultaneously from the pellet and followed zero order kinetics by the polymer controlled surface erosion mechanism to achieve sustained release profile 30 Satwara Rohan

Slide 31: 

31 Satwara Rohan

Sono crystallization: 

Sono crystallization The optimization of shape, size is profound important in disaggregation and dispersion efficiency of therapeutic aerosols. This study describes the development of a novel process to produce respirable sized particles and in vitro performance in model DPI and pMDI. Solutions of active pharmaceutical ingredients were atomized by either an electro hydrodynamic or high pressure driven aerosolized system. The aerosol droplets were subsequently collected in a non solvent of the drug. To initiate controlled primary nucleation Ultrasonic energy was introduced in system. Particle agglomerates were collected by filtering and drying. 32 Satwara Rohan

Conti…: 

Conti… The most important mechanism by which ultrasonic irradiation, or in sonication, can influence crystallization is ultrasonic Cavitation. Cavitation is particularly effective for inducing nucleation, and research shows dramatic improvements in reproducibility via such sononucleation. This approach has been used successfully to manipulate crystal size-distribution and, hence, to modify solid/liquid separation behaviour, washing and product purity, product bulk density, and powder flow characteristics. 33 Satwara Rohan

Application of Sonocrysatallization: 

Application of Sonocrysatallization Ultrasound Mediated Amorphous to Crystalline Transition (UMAX®) and Dispersive Crystallization with Ultrasound (DISCUS®) are being developed for the manufacture of respiratory particles for asthma and COPD drug products. The particleshave optimal size, shape, surface rugosity , surface free energy, crystallinity and stability. UMAX facilitates the preparation of both spheroidal and more regular shaped particles for Dry Powder Inhalation formulated with lactose (DPI) or Metered Dose Inhalation (MDI) with the particles suspended in hydrofluoroalkane (HFA) propellant. A large range of corticosteroids including fluticasone propionate (FP) can now be manufactured by “molecule-to-particle” sonocrystallization techniques. 34 Satwara Rohan

Pastillation: 

Pastillation ‘Pastillation’ to fabricate lipid based oral multiparticulate controlled release dosage forms for first time in pharmaceutical field is reported. Pastillation is a widely used technique in chemical, petrochemical and agrochemical industries for the solidification of dusty hazardous powders of chemicals into pastilles (hemispherical solidified units of uniformsize) which eases their handling. In this process, the drops of chemical substances in molten state are deposited on a cooled stainless steel surface for rapid solidification to generate pastilles of uniform dimensions. Depending on the size of the drops and the physical properties of the melt, the drops flatten to a certain extent. The solidified droplet, therefore, has the typical pastille-like shape. The production process can easily be carried out at large scale with the help of specially designed equipments called ‘Rotoformer’. 35 Satwara Rohan

Slide 36: 

36 Satwara Rohan

Application of pastillation : 

Application of pastillation Doxyphylline pastilles of PEG 400,4000 were prepared by Pastillation. This multiparticulate system has very good flow property and is very uniform size, weight and drug content and is able to sustain the drug release for a period of 24 h. This is a very simple method for producing lipid-based malt particulate system as compared to other available techniques (melt-extrusion and freeze Pelletization) This process is mainly useful for lipophilic drugs. 37 Satwara Rohan

Powder layering: 

Powder layering Powder layering involves the deposition of successive layers of dry powder of drug or excipients or both on preformed nuclei or cores with the help of a binding liquid. Powder layering involves the simultaneous application of the binding liquid and dry powder. Powder layering is mainly carried out in rotary granulator. Eg . Taste masking of acetaminophen by eudragit E PO has been done by powder layering technique. 38 Satwara Rohan

Process diagram: 

Process diagram 39 Satwara Rohan

Solution or suspension layering: 

Solution or suspension layering Solution/suspension layering involves the deposition of successive layers of solutions and/or suspensions of drug substances and binders on starter seeds, which may be inert materials or crystals/granules of the same drug. A starting grain or a pellet can be presented as the starting material. The pellet is built up to the required grain size by adding the layering substance one layer at a time. Powder and binders, suspensions or solutions make suitable layering substances. Thick layers can be applied to the starting grains, which, in the case of layers containing active ingredients, allow large amounts of active ingredient to be incorporated. Its carried out in fluidized bed processor. 40 Satwara Rohan

Slide 41: 

Eg.Duloxetine enteric coating is carried out with eudragit L 30 by suspension layering technique . 41 Satwara Rohan

Spray drying or congealing: 

Spray drying or congealing a) Spray drying: It is the process in which drugs in the suspension or solution without excipients are sprayed in to a hot stream to produce dry and more spherical particles. This process is commonly used for improving the dissolution rates; hence bioavailability of poorly soluble drugs . b) Spray congealing: It is the process in which a drug is allowed to melt, disperse or dissolve in hot melts of gums, waxes or fatty acids, and is sprayed into an air chamber where the temperature is kept below the melting point of the formulation components, to produce spherical congealed pellets. Both immediate and sustained released pellets can be prepared in this process depending on the physiochemical properties of the ingredients and other formulation variables . 42 Satwara Rohan

Slide 43: 

GTU questions Enlist the methods of spherical crystallization. Discuss any one method of spherical crystallization and write applications of spherical crystallisation. How does particle geometry affect pharma . processing? Discuss conventional and novel technology of spherical techniques in brief. 43 Satwara Rohan

References: 

References Patil SV et al. Spherical Crystallization: a Method to Improve Tabletabilty. Research J. Pharm. and Tech.2 (2): April.-June. 2009 Md. Akhlaquer Rahman et al. Recent Advances in Pelletization Technique for Oral Drug Delivery : A Review, Current Drug Delivery, 2009, 6, 122-129 Nikhil P. Jogad * A review: MUPS by extrusion spheronization Technique Journal of Pharmacy Research 2010, 3(8),1793-1797 M.M.Gupta1 et al, Spherical crystallization: a tool of particle engineering for making drug powder suitable for direct compression. Ijprd,2010,vov-1,issue-12,feb Parida R.et al Overview of spherical crystallisation in pharmaceuticals. International Journal of Pharma and BioSciencesVol.1/Issue-3/Jul-Sep.2010 Lavanya et al. Pelletization technology: a quick review ijpsr, 2011; Vol. 2(6): 1337-1355. Dali Shukla Pastillation: A novel technology for development of oral lipid based multiparticulate controlled release formulation.Powder Technology 209 (2011) 65–72 44 Satwara Rohan

Slide 45: 

Thank you…. 45 Satwara Rohan