SOLID STATE STUDIES IN PREFORMULATION

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SOLID STATE STUDIES IN PREFORMULATION:

SOLID STATE STUDIES IN PREFORMULATION CH.AVINASH Y11MPH443 I/II M.PHARMACY INDUSTRIAL PHARMACY CHALAPATHI INSTITUTE OF PHARMACEUTICAL SCIENCES 1

PREFORMULATION:

PREFORMULATION DEFINITION: It can be defined as an investigation of physical and chemical properties of new drug substance alone or in combination with other excipient . Preformulation studies focus on the physicochemical properties of the new compound that could affect drug performance and development of an efficacious dosage form. WHY IS PREFORMULATION IMPORTANT? It acts as a foundation for developing good formulations and successful commercial products. To increase drug stability. To improve drug bioavailability. To reduce drug excipient incompatibility . 2

GOALS OF PREFORMULATION: :

GOALS OF PREFORMULATION: To establish the necessary physicochemical parameters of new drug substances. To determine its kinetic rate profile. To establish its physical characteristics. To establish its compatibility with common excipients . 3

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The information that the preformulator must supply is: 1. Solubility of the compound. 2. What the preferred salt forms would be. 3. Does the compound form hydrates [i.e., it must be stored in given RH (relative humidity) ranges]? 4. What is the preferable polymorphic form? 5. Is the compound hygroscopic? 6. What is the pka of the compound? 7. What is the kinetic pH-profile? 8. What would be a preferable dissolution method (medium)? 9. Compatibility with other compounds. 10. Micromeritic considerations (shape factors and crystal habits, for instance). 4

INTRODUCTION:

INTRODUCTION The three states of matter are solid, liquid and gas (or vapour). In a sealed container vapours will diffuse to occupy the total space, liquids will flow to fill part of the container completely, but solids will retain their original shape unless a compressive force is applied to them. From this simple consideration it becomes clear that solids are unique because their physical form (the packing of the molecules and the size and shape of the particles) can have an influence on the way the material will behave. At normal room temperature and pressure the majority of drugs and excipients exist as solids, and so the study of solid state properties is of enormous pharmaceutical importance. 5

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Pharmaceutical Solids 6

Crystallinity and Polymorphism :

Crystallinity and P olymorphism Solid drug materials may occur as: 1. Amorphous (higher solubility) 2. Crystalline (higher stability) The amorphous or crystalline characters of drugs of great importance to 1. Its ease of formulation and handling. 2. Its chemical stability. 3. Its biological activity. 7

Amorphous form:

Amorphous form Amorphous drugs have atoms or molecules randomly placed as in a liquid. (particles without definite structure) 1. Randomly arranged atoms or molecules 2. Amorphous forms are typically prepared by: Rapid precipitation, Lyophilisation. 8

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Advantages: 1. Amorphous forms have higher thermodynamic energy than corresponding crystalline forms 2. Greater solubility’s as well as dissolution rates. Disadvantage : • Upon storage, amorphous solids tend to revert to more stable forms. This thermodynamic instability can occur during bulk processing or within dosage forms. Amorphous forms of drugs may be used: E.g. Novobiocin is inactive when administered in crystalline form, but when it is administered in the amorphous form, absorption from the gastrointestinal tract proceeds rapidly with good therapeutic response. 9

  Crystalline forms :

Crystalline forms Crystals are characterized by repetitious spacing of constituent atoms or molecules in a three dimensional array (substances of definite identifiable shape, fixed molecular order). Crystalline forms of drugs may be used because of greater stability than the corresponding amorphous form. For example: the crystalline forms of penicillin G as K or Na salt is considerably more stable and result in excellent therapeutic response than amorphous forms. 10

Crystal properties:

Crystal properties Crystal habit and the internal structure of a drug can affect bulk and physiochemical properties, which range from flowability to chemical stability. Habit is the description of the outer appearance of a crystal whereas the internal structure is the molecular arrangement within the solid. A single internal structure for a compound can have several different habits, depending on the environment for growing crystals. Characterization of solid form involves verifying that the solid is the expected chemical compound Internal structure Habit of the crystal 11

Examples of crystal habits:

Examples of crystal habits 12

Applications of crystallinity :

Applications of crystallinity The desired forms can be consistently manufactured; The effects of pharmaceutical manipulations are understood, e.g., granulation, milling and compression; and The effect of storage conditions on the dosage form can be evaluated and predicted, e.g., crystal growth in suspensions, creams and metered dose inhalers (MDIs). 13

Polymorphism :

Polymorphism Property of many drug substances to exist in more than one crystalline form with different space lattice arrangements. Two types of polymorphism: Enantiotropic : polymorph can reversibly change into other form by altering temperature and pressure, e.g. sulphur. Monotropic : unstable at all temperatures and pressures e.g. glyceryl stearates . Ex: Chloramphenicol exists in three polymophic forms A,B,C in which B form is most stable. 14

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Representation of two polymorphic forms of a crystal consisting of a molecule represented by a 'hockey-stick' shape. 15

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Structures of the polymorphs of estrone . Form III Form I Form II 16

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Polymorphs generally have different melting points, x-ray diffraction patterns and  solubility even though they are  chemically identical. Differences in the dissolution rates and solubility’s of different polymorphic forms of a given drug are very commonly observed. When the absorption of a drug is dissolution rate limited, a more soluble and faster-dissolving form may be utilized to improve the rate and extent of bioavailability. Although a drug substance may exist in two or more polymorphic forms, only one form is thermodynamically stable at a given temperature and pressure. The other forms would convert to the stable form with time. In general, the stable polymorph exhibits the highest melting point , the lowest solubility, and the maximum chemical stability. 17

Analytical methods for characterization of solid forms:

Analytical methods for characterization of solid forms Microscopy Fusion methods (hot stage microscopy) Differential scanning calorimetry (DSC/DTA) I nfrared spectroscopy x-ray powder diffraction Scanning electron microscopy T hermogravimetric analysis (TGA) Dissolution/solubility analysis 18

Thermal Analysis:

Thermal Analysis B asic principle: Heating or cooling can initiate dynamic changes in the solid state properties of a material. N umber of interrelated thermal analytical techniques can be used to characterize the salts and polymorphs of drugs which include: Differential thermal analysis (DTA), Differential scanning calorimetry (DSC), Thermogravimetric analysis (TGA), Hot stage microscopy (HSM) and Thermomechanical analysis (TMA). 19

Differential Scanning Calorimetry and Thermal Analysis :

Differential Scanning Calorimetry and Thermal A nalysis Differential thermal analysis (DTA) measures the temperature difference between the sample and a reference as a function of temperature or time when heating at a constant rate. Differential scanning calorimetry (DSC) is similar to DTA except that the instrument measures the amount of energy required to keep the sample at the same temperature as the reference i.e. it measures the enthalpy of transition . Depending on the type of change within the sample, the thermal event may be endothermic or exothermic . Endothermic - consume energy Exothermic - release energy to the surroundings. 20

Typical endothermic and exothermic processes in DTA/DSC :

Typical endothermic and exothermic processes in DTA/DSC 21

Hot stage microscopy (HSM):

Hot stage microscopy (HSM) This the issued observation of melting under a microscope equipped with a heated sample stage. The heating rate is controllable and up to three transitions can be registered. 22

X-Ray Powder Diffraction:

X-Ray P owder Diffraction Powder X-ray diffraction is a widely used tool for both the qualitative and quantitative analysis of different solid state forms. Analogous to light passing through a prism, as crystals are rotated through an X-ray beam, the beam is diffracted at characteristic angles . The powder X-ray diffraction pattern of the crystalline material is therefore described by a series of peaks at characteristic scattering angles . Conversely, the diffractogram of an amorphous material consists of one or more broad, diffuse maxima (amorphous halo or hump). 23

Powder X-ray diffractograms of a crystalline and an amorphous material:

Powder X-ray diffractograms of a crystalline and an amorphous material 24

Hygroscopicity :

Hygroscopicity Many drug substances, particularly the water soluble salt forms, have a tendency to absorb atmospheric moisture. Absorption and equilibrium moisture content can depend upon the atmospheric humidity, temperature, surface area, exposure, and the mechanism for moisture uptake. Hygroscopicity is classified into the four classes: 1. Slightly hygroscopic 2. Hygroscopic 3. Very hygroscopic 4. Deliquescent Measurement of Hygroscopicity 1. Dynamic vapour sorption method. 2. Isothermal microcalorimetry . 25

Particle size, shape and surface area:

Particle size, shape and surface area The particle size distribution of active ingredients and excipients is an important physical characteristic of the materials used to create pharmaceutical products. The size, distribution and shape of the particles can affect bulk properties, product performance, processability , stability and appearance of the end product. The link between particle size and product performance is well documented with regards to dissolution, absorption rates and content uniformity. 26

Particle size determination ::

Particle size determination : Sieving method Sedimentation method Optical microscopy Coulter counter Electron microscopy Laser light diffraction method 27

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A. Sieving method Particle size range between 50 and 1500μm . The sieve method finds application in dosage form development of the tablets and capsules. Normally 15 percent of fine powder should be present in granulated material to get proper flow of material and achieve good compaction. Advantages Inexpensive, simple, rapid and reproducible. Disadvantages a) Lower limit is 50μm b) If powder is not dry, aperture becomes clogged with particles leading to improper sieving. c) During attrition size reduction may occur. 28

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B. coulter counter method 1. Particle size ranging from 0.5 to 500μm is measured 2. Particle volume is measured and converted into the particle diameter. 3. Size is expressed as volume diameter , dv , it describes the diameter of the sphere having the same volume as that of asymmetric particle. 4. It is expensive method 5. Used in the study of particle growth in suspension and solutions C. Optical microscopy 1. Particle size range of 0.2-1μm can be measured by this method. 2. The size is expressed as projected diameter, which describes the diameter of a sphere having the same area as the asymmetric particle when observed under a microscope. 3. This method is used in the particle size determination of suspension, emulsion and aerosols. 29

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D. Sedimentation method 1. Sedimentation method may be used over a size range of 1 to 200μm. 2. In this method size is expressed as stokes's diameter, which describes the diameter of an equivalent sphere having the same rate of sedimentation as that of asymmetric particle. Sedimentation of particles is evaluated by different methods e.g. Andersen pipette method, balance method and hydrometer method. E . Scanning electron microscopy The scanning electron microscope ( SEM ) is a type of electron microscope that images the sample surface by scanning it with a high-energy beam of electrons A wide range of magnifications is possible, from about 10 times (about equivalent to that of a powerful hand-lens) to more than 500,000 times, about 250 times the magnification limit of the best light microscopes. 30

Surface area measurement methods:

Surface area measurement methods Importance of surface area measurement 1. Dissolution is a parameter of the surface area ( which is given by Noye’s Whiteny equation) 2. Surface area can also be quoted if the particle size is difficult to measure. Surface area measurement is done by: Adsorption method Air permeability method 31

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Adsorption method 1. Particles having large specific surface area are good adsorbents of gases and solutes from solutions. 2. Amount of gas adsorbed on the surface is function of the surface area of the powder. 3. This method is also used to measure the surface diameter. Air permeability method 1. This is the official method in I.P 2. Specific surface area is required for the proper absorption of the drugs e.g. griseofulvin , an antifungal antibiotic, should have surface area of not less than 13000 to 17000 cm2/g. Apparatus used: Fisher sub sieve sizer is commercially used for surface area measurement 32

Density and flow properties :

Density and flow properties True density It is the density of the material itself. It is defined as True density = The density is dependent upon the type of atoms in a molecule, arrangement of molecules in the sample Methods of measurement : Gas displacement method (Helium or Nitrogen) Liquid displacement. Helium displacement method: Helium penetrates the small pores and cervices therefore this method gives a value closer to true density. Helium pycnometer is used for this method. Weight of powder True volume of powder 33

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Bulk density It is defined as bulk density = Importance 1. The size of the capsules is determined by bulk volume for a given dose of material. 2. Bulk density is used to check the uniformity of the bulk chemicals 3. It helps in selecting the proper size of a container, packing material, mixing apparatus in the production of tablets and capsules. Mass of powder(w) Bulk volume ( Vb ) 34

Flow properties:

Flow properties 1. Irregular flow of the powders from the hopper produces tablets with non uniform weights. 2. Loss of content uniformity and dose precision 3. Flow properties depends upon particle size, shape, porosity and density of the bulk powder. Particle size 1.If particle size is very small flow is restricted owing to cohesion of particles. 2. As the particle size increases to optimum (400-800μm) the flow increases Nature of Particles 1. Smooth surface of the powder improves flow 2. Surface roughness leads to poor flow due to friction and cohesiveness. Moisture content 1.Higher moisture greater risk of cohesion and adhesion. 35

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Angle of repose Frictional forces leads to improper flow these forces are quantified by the angle of repose. Definition: Angle of repose is defined as the maximum angle possible between the surface of a pile of the powder on the horizontal surface. tanƟ = h/r 1. Lower the angle of repose, the better the flow property. 2. Decrease in particle size leads to a high angle of repose. 3. Lubricants at low concentration decreases the angle of repose, at high concentration enhance angle of repose <25 Excellent 25-30 Good 30-40 Passable >40 Very poor RELATIONSHIP B/W ANGLE OF REPOSE AND POWDER FLOW 36

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Carr’s index Carr’s compressibility index : Carr’s index (%) = Carr’s index Flow property 5-15 Excellent 12-16 Good 18-21 Fair to passable 23-35 Poor 33-38 Very poor >40 Extremely poor Tapped density – bulk density Tapped density x100 37

Relationship between angle of repose, Carr's index of a powder and its flow characteristics:

Relationship between angle of repose, Carr's index of a powder and its flow characteristics 38

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Hausner’s index Hausner ratio: has been defined by Hausner : Hausner ratio = Value less than 1.25 indicates good flow (= 20%Carr), Value greater than 1.5 indicates poor flow (=33% Carr). Between 1.25 and 1.5, if glidant is added normally improves flow. > 1.5 if glidant is added doesn’t improve flow. Tapped density bulk density x100 39

Solubility analysis:

Solubility analysis The solubility of drug is an important physicochemical property because it effects the bioavailability of the drug, the rate of drug release into dissolution medium and consequently, the therapeutic efficiency of the pharmaceutical product. The solubility of the molecules in various solvents is determined as a first step. This information is valuable in developing a formulation. Solubility is usually determined in variety of commonly used solvents and some oils if the molecules are lipophillic . Common solvents used for solubility determination are :- Water Isopropyl Alcohol Tweens Glycols Polysorbates Glycerine Castor Oil Sorbitol Peanut Oil Benzyl Alcohol Sesame Oil Ethyl Alcohol Buffer at various pHs Methanol 40

The U.S. Pharmacopeia (USP) gives the following definitions of solubility:

The U.S. Pharmacopeia (USP) gives the following definitions of solubility Descriptive Term Parts of Solvent Required for 1 Part of Solute Very soluble Less than 1 Freely soluble From 1 to 10 Soluble From 10 to 30 Sparingly soluble From 30 to 100 Slightly soluble From 100 to 1,000 Very slightly soluble From 1,000 to 10,000 Practically insoluble or insoluble 10,000 and over 41

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Aqueous Solubility :- The availability of a drug is always limited and the preformulation scientist may only have 50 mg. Solubility dictates the ease with which formulation  for oral gavages and intravenous injection studies in animals are obtained. The pKa gives the information of pH to maintain solubility and to choose salts required to achieve good bioavailability from the solid state and improve stability and powder properties. Intrinsic  Solubility (Co) :- An increase in solubility in acid compared to aqueous solubility suggests a weak base and an increase in alkali, a weak acid an increase in acidic. In this case there will be two pKa’s , one acidic & one basic. The solubility obtained in acid for a weak acid or alkali for a weak base can be assured to be the intrinsic solubility (Co.) 42

pKa determination :

pKa determination It is defined as the negative logarithm of dissociation constant. Determination of the dissociation constant for a drug capable of ionization within a PH range of  1 to 10 is important since solubility and consequently absorption, can be altered by changing pH. The Henderson- Hasselbalch equation provides an estimate of the ionized and un ionized drug concentration at a particular pH. For acidic compounds pH = pKa + log  (un-ionized drug]) / [ionized drug]) For basic compounds: pH = pKb + log (un-ionized drug) / (ionized drug) The larger the value of pKa , the smaller the extent of dissociation. A weak acid has a pKa value in the approximate range −2 to 12 in water. Acids with a pKa value of less than about −2 are said to be strong acids . 43

Salts:

Salts A major improvement in solubility can be achieved by forming a salt In some cases, salts prepared from strong acids or bases are freely soluble but very hygroscopic. This does lead to instability in tablet or capsule formulations. It is often better to use a weaker acid or base to form the salt, provided any solubility requirements are met. A less soluble salt will generally be less hygroscopic and form less acidic or basic solutions. Injections should ideally lie in the pH range 3-9 to prevent vessel or tissue damage and pain at the injection site. Oral syrups should not be too acidic, to enhance palatability. 44

Potential pharmaceutical salts:

Potential pharmaceutical salts 45

FDA-approved commercially marketed salts.:

FDA-approved commercially marketed salts. 46

Partition coefficient :

Partition coefficient Partition Coefficient (oil/ water) is a measure of a drug’s lipophilicity and an indication of its ability to cross cell membranes. It is defined as the ratio of unionized drug distributed between the organic and aqueous phases at equilibrium. P o/w = (C oil / C water) equilibrium. Although partition coefficient data alone does not provide understanding of in vivo absorption, it helps in characterizing the lipophilic / hydrophilic nature of the drug. Since biological membranes are lipoidal in nature. The rate of drug transfer for passively absorbed drugs is directly related to the lipophilicity of the molecule. The partition coefficient is commonly determined using an oil phase of octanol or chloroform and water. Drugs having values if P much greater than 1 are classified as lipophilic , whereas those with P much less than 1 are indicative of a hydrophilic drug. 47

Solid state stability:

Solid state stability Chemical instability normally results from either of the following reaction :- hydrolysis, oxidation, photolysis and pyrolysis . Ex: Esters, lactase and to lesser extent, amides are prone to solvolysis . Elevated temperature studies:- The elevated temperatures commonly used are 40, 50, and 60 degree centigrade with ambient humidity. The samples stored at highest temperature are observed weekly for physical and  chemical changes and compared to an appropriate control . If a substantial change is seen, samples stored at lower temperature are examined . If no changes are seen after 30 days at 60 degree centigrade, the stability is excellent. 48

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Stability under high humidity conditions :- Solid drug samples can be exposed to different relative humidity conditions by keeping them in laboratory desiccators containing saturated solutions of various salts. The closed desiccators in turn are kept in oven to provide constant temperature. The preformulation data of this nature are useful in determining if the material should be protected and stored in controlled low humidity environment or if non aqueous solvent be used during formulation. Photolytic stability :- Many drugs fade or darken on exposure to light. Exposure of drug to 400 and 900 foot-candles of illumination for 4 and 2 week periods respectively is adequate to provide some idea of photosensitivity. Resulting data may be useful in determining if an amber colored container is required or if color masking should be used in the formulation . 49

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Stability to Oxidation :- Drug’s sensitivity to oxidation can be examined by exposing it to atmosphere of high oxygen tension. Usually a 40% oxygen atmosphere allows for rapid evaluation. Samples are kept in desiccators equipped with three-way stop cocks, which are alternatively evacuated and flooded with desired atmosphere. The process is repeated 3 or 4 times to ensure 100% desired atmosphere. Results may be useful in predicting if an antioxidant is required in the formulation or if the final product should be packaged under inert atmospheric conditions 50

CONCLUSION:

CONCLUSION Solid state characterization of a Drug is the foundation of a knowledge base that leads ultimately to the development of a stable, efficacious dosage form. Unfortunately, many pharmaceutical companies have learned from experience the importance of a timely and thorough evaluation of solid state properties. 51

REFERENCES :

REFERENCES Leon Lachman , Lieberman’s The Theory and practice of industrial pharmacy; pg 171-194. M.E. Aulton’s Pharmaceutics The Science of Dosage Form Design S econd Edition; pg 113-151 Mark Gibson’s Pharmaceutical Preformulation and Formulation Preformulation By Dr. Thomas Schultz J.Swarbrick’s Encyclopaedia of pharmaceutical technology ; 3 rd edition; volume 3; p 2935-2944. Martin’s Physical Pharmacy and Pharmaceutical Sciences 5 th edition Carstensen J.T. pharmaceutical Preformulation . 1998. 52

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THANK U 53

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