SOLID DISPERSIONS

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solid dispersion is a widely used successful technique to increase the solubility of poorly aqueous soluble drugs and to enhance their permeability. in this the drug molecules in their solid state are dispersed in an inert hydrophilic matrix.

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SOLID DISPERSIONS:

SOLID DISPERSIONS 1 Course: M.Pharmacy Prepared By: K.Spurthi QIS College of p harmacy, Ongole

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CONTENTS INTRODUCTION NOYES-WHITNEY EQUATION POSSIBILITIES TO ENHANCE DISSOLUTION DEFINITION OF SOLID DISPERSIONS TYPES OF CARRIERS TYPESOF SOLID DISPERSIONS ADVANTAGES OF SOLID DISPERSIONS PREPARATION OFSOLID DISPERSIONS CHARACTERISATION OFSOLIDDISPERSIONS APPLICATIONS REFERENCES 2

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INTRODUCTION Oral route drug administration - common and preferred method -convenience and ease of ingestion. But can be a problematic and inefficient mode of delivery for a number of reasons. Limited drug absorption resulting in poor bioavailability is paramount amongst the potential problems. 3

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Drug must first dissolve in gastric and/or intestinal fluids reach systemic circulation. Drug absorption from the gastrointestinal (GI) tract can be limited by a variety of factors: Poor aqueous solubility Poor membrane permeability of the drug molecule. A drug with poor aqueous solubility exhibit dissolution rate limited absorption. Drug with poor membrane permeability will typically exhibit permeation rate limited absorption. . 4

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The oral bioavailability of active agents can be improved by: (i) Enhancing solubility and dissolution rate of poorly water-soluble drugs and (ii) Enhancing permeability of poorly permeable drugs. Solid dispersion technologies improve the dissolution characteristics of poorly water-soluble drugs and in turn their oral bioavailability. 5

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Where, dc/dt=rate of dissolution A=surface area available for dissolution D=diffusion coefficient of compound Cs=solubility of compound in dissolution medium C=concentration of drug in medium at time ‘t’ h=thickness of diffusion boundary layer adjecent to surface of dissolving compound. 7

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POSSIBILITIES TO ENHANCE DISSOLUTION 1. Increase the surface area available for dissolution 2. Improvement of solubility through formulation approaches. 1.Increase the surface area available for dissolution: This can be achieved by decrease in the size of the particle Microionization But , it has several disadvantages like, less oppurtunity to control particle size , shape, morphology, surface properties, electrostatic charges of final particles. 8

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2. Improvement of solubility through formulation approaches: Various approaches have been developed for solubility enhancement. Salt formation, Complexation with cyclodextrins , Solubilization of drugs in solvent(s), and particle size reduction Use of pro drug Alteration in pH 9

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Formation of solid dispersions with water soluble carriers is suitable method of choice. It offers a variety of processing and excipient options that allow for flexibility in preparing the dosage form. Drug used for solid dispersion need not be in Microionized state (which has many disadvantages), a part of drug can be molecularly dispersed in the matrix. Solid dispersion on exposure to aqueous media causes increase in surface area. 10

SOLID DISPERSIONS:

SOLID DISPERSIONS Definition: The term solid dispersion refers to a group of solid products consisting of at least two different components ,generally a hydrophilic matrix and hydrophobic drug . The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles(clusters) or in crystalline particles 11

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. Why we are using this technology ? To enhance the oral absorption and bioavailability of BCS Class II drugs . In the Biopharmaceutical Classification System (BCS) drugs with low aqueous solubility and high membrane permeability are categorized as Class II drugs. The use of solid dispersion technology improves the dissolution characteristics of poorly water-soluble drugs and in turn their oral bioavailability. 12

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On exposure of Solid dispersion to aqueous media Carrier dissolves Releases drug as fine collidal particles Results in increased surface area Increase in dissolution rate Increase in Bio availability 13

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Selection of carriers Carriers melted at elevated temperatures and drugs dissolved in molten carriers. Surface-active agents are substances that, at low concentrations adsorb onto the surfaces or interfaces of a system, and alter the surface or interfacial free energy and the surface and the interfacial tension. Surface-active agents have a characteristic structure, possessing both polar (hydrophilic) and non-polar (hydrophobic) regions in the same molecule. The surface active carriers are said to be amphipathic in nature. 14

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Characteristics of carriers : Readily soluble in water and in gastrointestinal fluids. Physiologically inert. Melting point not much higher than drug. Thermal stability at melting temperature. Relatively low vapour pressure, and Should have high molecular weight to fulfill the requirement of the host. They should be nontoxic. 15

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Carriers used in solid dispersions are of two types : 1. Crystalline carriers 2. Polymeric carriers 1. Crystalline carriers : Ex: urea, sugars.( Dextrose, sucrose, lactose) The first prepared solid dispersion (Sekiguchi & Obi 1961) consisted of sulfathiazole and urea as matrix, prepared at eutectic composition by fusion method. 2. Polymeric carriers: ex: PEG, PVP, HPMC, PVC, Crospovidone etc., 16

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Poly ethylene glycol (PEG) OH-CH2-CH2-[O-CH2-CH2]n-OH Water soluble synthetic polymer obtained by catalystic condensation of ethylene oxide and water. Used by melting method. After melting difficult step is hardening of melts. Limitations: Difficulty in pulverizing & sifting the product (soft, tacky, poor flow properties of powders) (pulverizing to go for subsequent formulation in to power filled capsules or compressed tablets.) 17

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2. Poly vinyl pyrolidine (PVP): Mostly used as binder, coating agent in solid dosage forms. As suspending agent, stabilizing agent, & as viscosity enhancer in liquid formulations. Tg of PVP is high hence not suitable for preparation by melting method. (Tg: function of chain flexibility. At this the mechanical behavior of polymer changes from rigid & brittle to tough & leathery. ) Soluble in organic solvents hence usedby solvent method. 18

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3.Hydroxy propyl methyl cellulose(HPMC): Mixed ethers of cellulose in which 16.5 – 30% of hydroxyl groups are methylated & 4-32% are derivatised with OH groups. Mol.wt: 10,000-15,00,000 Soluble in water, mixture of ethanol-dichloromethane & methanol- dichloromethane. Engers et al prepared itraconazole solid dispersion with different polymers at varied concentrations 1:2(itraconazole:Hpmc) showed best results. 19

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4.Poly vinyl alcohol(PVA): These are water soluble synthetic polymers with formula ( C2H4O)n. n for commercially available materials lies between 500-5000. Solid dispersions of Nifidipine were prepared with carrier mixture consisting of nicotinamide & PVP. HPMC or PVP in drug:nicotinamide:polymerin 1:3:1 Those prepared with PVA showed 20 times 20

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TYPES OF SOLID DISPERSIONS These are mainly classified in to 4 types I. Simple eutectic mixtures II. Solid solutions III. Glass solution and suspension IV. Amorphous precipitations in a crystalline carrier. 21

TYPES OF SOLID DISPERSIONS:

TYPES OF SOLID DISPERSIONS Eutectics: The first type of solid dispersion prepared Amorphous precipitations in crystalline matrix : Rarely encountered Solid solutions: Continuous solid solutions: Miscible at all composition, never prepared. Discontinuous solid Solutions: Partially miscible, 2 phases even though drug is molecularly dispersed. Substitutional solid Solutions: Molecular diameter of drug (solute) differs less than 15% from the matrix (solvent) diameter. 22

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d . Interstitial solid solutions: Drug (solute) molecular diameter less than 59% of matrix (solvent). 4 . Glass suspension : Particle size of dispersed phase dependent on cooling/evaporation rate. Obtained after crystallization of drug in amorphous matrix. 5. Glass suspension : Particle size of dispersed phase dependent on cooling/evaporation rate many solid dispersions are of this type. 6. Glass solution : Requires miscibility or solid solubility, complex formation or upon fast cooling or evaporation during preparation, many examples especially with PVP. 23

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Simple eutectic mixtures These are prepared by rapid solidification of the fused melt of two components that show complete liquid miscibility and negligible solid solid solubility. Thermodynamically, such a system is an intimately blended physical mixture of its two crystalline components. Ex. Chloremphenicol-urea; Paracetamol urea; Griseofulvin & Tolbutamide -PEG 2000. T A– M.P. of solid A T B – M.P. of solid B TE – Eutectic Point 24

Eutectics:

Eutectics 25

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Amorphous precipitations in a crystalline carrier The difference between this group of solid dispersions and the simple eutectic mixture is that the drug is precipitated out in an amorphous form in the former as opposed to a crystalline form in the latter. Ex: Sulfathiazole was precipitated in the amorphous form in crystalline urea. 26

Amorphous precipitations in crystalline matrix :

Amorphous precipitations in crystalline matrix 27

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Solid solutions In a solid solution the two components crystallize together in a homogeneous one phase system . The particle size of the drug in the solid solution is reduced to its molecular size. Thus, a solid solution can achieve a faster dissolution rate than the corresponding eutectic mixture. According to the extent of miscibility of the two components, they may be classified as continuous or discontinuous. In continuous solid solutions, the two components are miscible in the solid state in all proportions. 28

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b . Discontinuous solid Solutions: Partially miscible. 2 phases even though drug is molecularly dispersed. 30

Discontinuous solid Solutions:

Discontinuous solid Solutions 31

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c. Substitutional solid Solutions: Molecular diameter of drug (solute) differs less than 15% from the matrix (solvent) diameter. d . Interstitial solid solutions: Drug (solute) molecular diameter less than 59% of matrix (solvent). 32

Substitutional solid Solutions:

Substitutional solid Solutions 33 33

Interstitial solid solutions:

Interstitial solid solutions 34 34

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Glass solutions and suspensions A glass solution is a homogeneous glassy system in which a solute dissolves in the glassy system . refers to a mixture in which precipitated particles are suspended in a glassy solvent , it is characterized by transparency and brittleness below the glass transition temperature. Glasses do not have sharp melting points, instead, they soften progressively on heating. The lattice energy, which represents a barrier to rapid dissolution, is much lower in glass solutions than in solid solutions. 36

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Advantages of solid dispersion:

Advantages of solid dispersion 1. Particles with reduced particle size : Molecular dispersions, as solid dispersions, represent the last state on particle size reduction. Poorly water soluble drug dissolved in highly soluble carrier. Increased surface area Increased dissolution rate Iincreased bioavailability 38

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2. Particles with improved wettability: Enhancement of drug solubility is related to increase in the wettability of drug in solid dispersion. Carriers can influence drug dissolution profile by direct dissolution or co-solvent effect. Carriers without surface activity can also influence drug wettability. ex: urea Carriers with surface activity ex: cholic acid, bile salts. 39

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3.Particles with higher porosity: Particles in solid dispersions have been found to have a higher degree of porosity. Increase in porosity α increase in drug release. Increase in porosity also depends on the carrier properties. solid dispersions containing linear polymers produce larger and more porous particles than those containing reticular polymers and, therefore, result in a higher dissolution rate. 40

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4. Drugs in amorphous state: Poorly water soluble crystalline drugs, when in the amorphous state tend to have higher solubility. No energy is required to break up the crystal lattice during the dissolution process. In solid dispersions, drugs are presented as supersaturated solutions after system dissolution. 41

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Preparation of solid dispersions: A. Fusion method The first solid dispersions were prepared by fusion method. It consisted of sulfathiazole and urea as a matrix. They were melted using a physical mixture at the eutectic composition ,(to obtain simultaneous crystallization of drug and matrix during cooling) followed by a cooling step. This procedure resulted in solid dispersions of type I. Poly(ethylene glycol) (PEG) is a hydrophilic polymer often used to prepare solid dispersions with the fusion method. PVP is frequently applied as matrix in fusion method. 42

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Limitations can only be applied when drug and matrix are compatible and when they mix well at the heating temperature. A problem can arise during cooling when the drug-matrix miscibility changes. In this case phase separation can occur. Degradation of the drug and or matrix can occur during heating to temperatures necessary to fuse matrix and drug. 43

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Vacuum: removal of residual solvents/water 44

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B. Hot melt extrusion Intense mixing of the components is induced by the extruder. Melt extrusion offers the potential to shape the heated drug-matrix mixture into implants, ophthalmic inserts, or oral dosage forms. Just like in the traditional fusion process, miscibility of drug and matrix can be a problem. High shear forces resulting in high local temperatures in the extruder be a problem for heat sensitive materials. 45

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compared to the traditional fusion method, this technique offers the possibility of continuous production. C. Solvent method This involves 2 steps for the preparation of solid dispersions 1.Preparation of a solution containing both matrix material and drug. 2. The removal of solvent(s) resulting in formation of a solid dispersion. Mixing at the molecular level leads to optimal dissolution properties , hence it is preferred . 46

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Using the solvent method, the pharmaceutical engineer faces two challenges. 1. To mix both drug and matrix in one solution , which is difficult when they differ significantly in polarity. 2. To prevent phase separation , e.g. crystallization of either drug or matrix, during removal of the solvent(s). Dissolving Drug & matrix together in a solution: Mixing at the molecular level is preferred, because this leads to optimal dissolution properties. To minimize the drug particle size, the drug and matrix have to be dispersed in the solvent as fine as possible 47

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Various strategies to dissolve lipophilic drug and hydrophilic matrix material in one solution. 1. Low drug concentrations are used to dissolve both drug and matrix material in water . but this requires evaporation of tremendous amounts of solvent, making the process expensive and impractical. Solubilisers like cyclodextrins or surfactants like Tween80 ® increase the aqueous solubility of the drug substantially. These may significantly change the physical properties of the matrix (e.g., decrease of Tg). 48

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In addition, they may even be toxic. 2. Chloroform or dichloromethane have been used to dissolve both drug and PVP as matrix simultaneously. However, according to the ICH-Guidelines, these solvents belong to Class I , comprising the most toxic solvents. Therefore, the use of these solvents is unacceptable. 3. The last strategy for the dissolution of both drug and matrix is the use of solvent mixtures. Water and ethanol or dichloromethane and ethanol have been used for this purpose. 49

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Dissolution of drug and matrix in these mixtures is not always possible in the required concentration or ratio. Prevention of phase separation: e.g. crystallization of either drug or matrix, during removal of the solvent(s). Drying at high temperatures speeds up the process and reduces the time available for phase separation. On the other hand, at high temperatures the molecular mobility of drug and matrix remains high , favoring phase separation (e.g., crystallization). 50

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To dry the solutions, vacuum drying is often used The solution is dried by the application of vacuum and moderate heating. Vacuum drying at elevated temperature bears the risk of phase separation because the mobility of drug and matrix decreases slowly. Another drying technique is spray drying. The solution is dispersed as fine particles in hot air. Due to the large specific surface area offered by the droplets, the solvent rapidly evaporates and the solid dispersion is formed within seconds, which may be fast enough to prevent phase separation. 52

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Spray drying usually yields drug in the amorphous state however sometimes the drug may have (partially) crystallized during processing. An alternative to these drying techniques is freeze drying . This technique is poorly exploited for the preparation R:low freezing temperature of most organic solvents . Sublimation during freeze drying is only possible when the solvent stays frozen. In addition when the formation of a glass is envisaged, the sample temperature should be kept below the Tg. Therefore, low sample temperatures are required which slows down the process. 53

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To obtain a lyophiliation process of acceptable duration, the solvent should have a sufficiently high vapour pressure. Dimethylsulphoxide (DMSO) has a high melting temperature but it has a very low vapour pressure. Therefore, DMSO is not suitable as a solvent for freeze drying. A suitable solvent that meets both requirements is 2- methyl-2-propanol or tertiary butanol (TBA), because it has a high melting temperature as well as a high vapour pressure. 54

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Also mixtures of solvents can be considered. Example, water and DMSO have melting points of 0°C and 19°C, the mixture has eutectic points below - 60°C. The sample temperature of such a mixture should be kept below this value, which causes a slow sublimation. Advantages of freeze drying Drug is subjected to minimal thermal stress during the formation of the solid dispersion. Risk of phase separation is minimized as soon as the solution is vitrified. 55

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An even more promising drying technique is spray-freeze drying. The solvent is sprayed into liquid nitrogen or cold dry air and the frozen droplets are subsequently lyophilized. The large surface area and direct contact with the cooling agent result in even faster vitrification , thereby decreasing the risk for phase separation to a minimum. spray freeze drying offers the potential to customize the size of the particle to make them suitable for further processing or applications like pulmonary or nasal administration 56

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D. Electrostatic spinning process Drug-matrix solution is pumped through an orifice and then subjected to an electrical field to form fibres with a diameter of micro- or nano-scale. This process is restricted since only a few high molecular weight materials can form fibres. After rapid evaporation of the solvent, the fibres can be directly used or milled and further processed. F. Evaporative precipitation into aqueous solutions (EPAS) Used to coat a colloidal suspension of carbamazepine with block-copolymers as stabilizing surfactants. 57

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Solution of drug in dichloromethane was sprayed in an aqueous solution containing polymeric surfactants as stabilizers. The obtained colloidal suspension was spraydried, freeze dried or spray freeze dried, resulting in solid dispersions of type IV/V. Amorphous state of the drug was best preserved with the spray freeze drying process. G. Supercritical fluid method Supercritical fluid methods are mostly applied with carbon dioxide (CO2), which is used as either a solvent for drug and matrix or as an anti-solvent . 58

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This technique does not require the use of organic solvents and since CO2 is considered environmentally friendly, this technique is referred to as ‘solvent free’. The technique is known as Rapid Expansion of Supercritical Solution (RESS). This technique is very limited, because the solubility in CO2 of most pharmaceutical compounds is very low (<0.01wt-%) and decreases with increasing polarity. They used a technique that is called the Gas-Anti-Solvent technique (GAS) or Precipitation from Gas Saturated Solutions (PGSS). 59

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The solution is brought into contact with compressed CO2. The conditions are chosen so that CO2 is completely miscible with the solution under supercritical conditions. Drug and matrix will precipitate upon expansion of the solution. When the volume of the solution expands the solvent strength (i.e. the ability to dissolve the drug) decreases. This results in precipitation of matrix and drug. Since this technique is often applied with PEG as matrix, that results in formation of a solid dispersion with a crystalline matrix 60

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The second type of precipitation technique involves the spraying of a solution containing drug and matrix through a nozzle into a vessel that contains a liquid or supercritical anti-solvent. The supercritical anti-solvent rapidly penetrates into the droplets, in which drug and matrix become supersaturated, crystallize and form particles. This process is known as Precipitation with Compressed Anti-Solvent (PCA). The critical step in these precipitation techniques might be the dissolution of drug and matrix in one solution. 61

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H. Melt agglomeration method In this method binder acts as a carrier. These can be prepared by two ways. Either by Heating binder, drug and excipient to a temperature above the melting point of the binder; or By spraying a dispersion of drug in molten binder on the heated excipient by using a high shear mixer35. A rotary processor is alternative equipment for melt agglomeration, because it is easy to control temperature .and 63

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Higher binder content can be incorporated in to agglomerates. In addition the melt in procedure also results in homogenous distribution of drug in agglomerate. Larger particles results in densification of agglomerates while, fine particle cause complete adhesion . The mass to bowl shortly after melting attributed to distribution and coalescence of the fine particles. 64

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I. Supercritical fluid impregnation The drug is dissolved in a supercritical fluid and exposed to solid matrix material that swells and absorbs the supercritical solution. By varying the pressure and the time of exposure, the diffusion process can be controlled. The absorption stops when the pressure is reduced . This process is investigated for poly (methyl methacrylate) but can be applied for other polymers as well. 66

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Solid Solution Preparation Most processes to make solid solutions involve the formation of a true solution followed by quenching Cooling Solvent removal Other processes include mechanical activation, precipitation. These routes can be used for clinical manufacture, other analogous processes can be used for screening (e.g. batch solvent casting) 67

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Characterization of solid dispersion A. Detection of crystallinity in solid dispersions: Many techniques are available which detect the amount of crystalline material in the dispersion. The amount of amorphous material is never measured directly but is mostly derived from the amount of crystalline material in the sample. But, it will not be revealed whether the drug is present as amorphous drug particles or as molecularly dispersed molecules. 69

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Currently, the following techniques are available to detect (the degree of) crystallinity Powder X-ray diffraction : Sharper diffraction peaks indicate more crystalline material. Infrared spectroscopy (IR): Sharp vibrational bands indicate crystallinity. Fourier Transformed Infrared Spectroscopy (FTIR): Detect crystallinities ranging from 1 to 99% in pure material. Water vapour sorption: Discriminates between amorphous and crystalline material when the hygroscopicity is different 70

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This method requires accurate data on the hygroscopicity of both completely crystalline and completely amorphous samples. Isothermal Microcalorimetry: Measures the crystallization energy of amorphous material that is heated above its glass transition temperature (Tg). Dissolution Calorimetry: Measures the energy of dissolution, which is dependent on the crystallinity of the sample. Dissolution of crystalline material is endothermic. Dissolution of amorphous material is exothermic. 71

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Macroscopic techniques: Measure mechanical properties that are different for amorphous and crystalline material can be indicative for the degree of crystallinity . Density measurements and Dynamic Mechanical Analysis (DMA): Determine the modulus of elasticity and viscosity and thus affected by the degree of crystallinity. B. Detection of molecular structure in amorphous solid dispersions The properties of a solid dispersion are highly affected by the uniformity of the distribution of the drug in the matrix. 72

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The stability and dissolution behaviour could be different for solid dispersions that do not contain any crystalline drug particles, i.e. solid dispersions of type V and VI or for type II and III. very few studies focus on the discrimination between amorphous incorporated particles versus molecular distribution or homogeneous mixtures. Confocal Raman Spectroscopy: Used to measure the homogeneity of the solid mixture of ibuprofen in PVP. A standard deviation in drug content smaller than 10% was indicative of homogeneous distribution. 73

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IR or FTIR: Extent of interactions between drug and matrix can be measured. The interactions are indicative for the mode of incorporation of the drug. Temperature Modulated Differential Scanning Calorimetry (TMDSC): Can be used to assess the degree of mixing of an incorporated drug. Due to the modulation , reversible and irreversible events can be separated. The sensitivity of TMDSC is higher than conventional DSC Therefore this is used to assess the amount of molecularly dispersed drug. 74

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Amount of Crystalline material Measured by DSC. In DSC samples are heated with constant heating & amount of energy necessary for that is detected. With DSC the temperature at which the thermal events occur can be detected. Thermal events can be a glass to rubber transition, re crystallization, melting or degradation. The melting energy can be used to detect the amount of crystalline material. 75

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Interaction between drug & carrier A thin layer chromatography is carried out to study interaction between drug & carrier to conform the chemical stability of solid dispersions prepared. Mobile phase : Acetonitrile : Water : Acetic acid : Triethylamine (47:53:0.1:0.03). Drug content uniformity From each batch of solid dispersions take equivalent to 25 mg of drug & dissolve in 100ml of methnol & measure the absorbance using UV-Visible Spectrophotometer for analyzing drug content uniformity. 76

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Drug release study It is carried out using USP XXIII dissolution apparatus. 900ml of pH 7.4 phosphate buffer is used as dispersion medium. Solid dispersion equivalent to 100mg drug is taken in hard gelatin capsule. Stirrer adjusted to 75 rpm & temperature to 37°c . 5ml of aliquot samples withdrawn at different time intervals & analyzed after suitable dilutions using UV-Visible spectrophotometer. Sink conditions were maintained. 77

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% of drug dissolved at various time intervals was calculated & plotted against time. APPLICATIONS Application of fast release solid dispersions for non oral routes needs to be investigated. The fast release of a highly lipophilic drug in the pulmonary mucosa could lead to rapid local action (or) rapid systemic absorption. To obtain a homogeneous distribution of a small amount of drug in solid state. To stabilize the unstable drug. To dispense liquid or gaseous compounds in a solid dosage. 78

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To formulate a fast release primary dose in a sustained released dosage form. To formulate sustained release regimen of soluble drugs by using poorly soluble or insoluble carriers. To reduce pre systemic inactivation of drugs like morphine and progesterone. Polymorphs in a given system can be converted into isomorphous , solid solution, eutectic or molecular addition compounds. 79

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REFERENCES 1 . SOLID DISPERSIONS: A REVIEW DHIRENDRA K, LEWIS S*, UDUPA N AND ATIN K Manipal College of Pharmaceutical Sciences, Manipal, Karnataka, India 2.RESEARCH JOURNAL OF PHARMACY AND TECHNOLOGY (MARCH-2011) 3.MARTIN’S PHYSICAL PHARMACY AND PHARMACEUTICALSCIENCES Sixth Edition. 4.Indian Journal of Novel Drug Delivery. 80

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