All the medicinal products or dosage forms will contain the drug plus a variety of additives or excipients whose role is to enhance the product performance without altering the stability and pharmacology of the drug. It is therefore, a general rule that patients are never administered a drug but rather a medicinal product that contains the drug. Pharmaceutical development of a medicinal product must retain the drugs promising invitro pharmacological activity and provide a predictable in-vivo response.
The marketed product must be stable, correctly packaged, labeled and easily administered, preferably by self administration. The development of pharmaceutical product involves multiple skills, processes and stages and is, therefore, a large undertaking requiring extensive resources. The development of medicinal product consists of several stages such as Preformulation The study involves Characterization of physicochemical properties and includes extensive study of Physiochemical characteristics of the drug Solubility characteristics of the drug.
Drug-Excipient Compatibility Analytical method developments Stability studies Formulation development Formulation development is a continuing process which is attempted by the manufacturer after NDA consideration of Application for the medicinal product. The dose of the drug and the route of administration are important in determining the required modifications and involves development of 2 Injectable drug product Topical drug product Oral drug product Vaginal drug products Nasal drug products Pulmonary drug products Final drug product.
Considerations in the development of final dosage form include the following Color, shape, size, taste, viscosity, sensitivity, skin feel, and physical appearance of the dosage form Size and shape of package or container Production equipment Production site Country of origin in which the drug is to be manufactured Country in which the medicine will be marketed. Definition Preformulation studies are defined as the application of biopharmaceutical principles to the physicochemical parameters of drug substance that are characterized with the goal of designing optimum drug delivery system.
Preformulation is the characterization of the physical and chemical properties of the active drug substances and dosage forms. The therapeutic indication of the drug and the route of administration dictate the type of drug product or drug delivery system that needs to be developed. The characterization of drug and its excipient compatibility information decides many of the subsequent events and approaches in formulation development. Preformulation activities are usually performed during the preclinical stage. However these activities may continue in to phase I and phase II studies.
During 3 preformulation studies preformulation scientist. I) the following information is obtained by the Physiochemical characteristics of the drug II) Solubility characteristics of the drug IV) Drug-Excipient Compatibility V) Analytical method developments VI) Stability studies I) PHYSIOCHEMICAL CHARACTERISTICS OF THE DRUG: The physical characterization of the drug involves characterization of various physical properties and involves Particle Size, Shape, and surface area Powder flow properties Crystalline properties and Polymorphism.
Saturation Hygroscopicity Melting point pKa 1) PARTICLE SIZE, SHAPE, AND SURFACE AREA In general, each new drug candidate should be tested during Preformulation with the smallest particle size as is practical to facilitate preparation of homogeneous samples and maximize the drug’ s surface area for interactions. Various chemical and physical properties of drug substances are affected by their particle size distribution and shapes. The effect is not only on the physical properties of solid drugs but also, in some instances, on their biopharmaceutical behavior.
It is generally recognized that poorly soluble drugs showing a dissolution- rate limiting step in the absorption process will be more readily bio available when administered in a finely subdivided state rather than as a coarse material. 4 In case of tablets, size and shape influence the flow and the mixing efficiency of powders and granules. Size can also be a factor in stability: fine materials are relatively more open to attack from atmospheric oxygen, the humidity, and interacting excipient than the coarse materials. – Determination of particle size -Determination of surface area Particle size Determination:
Though microscopy is the simplest technique of estimating size ranges and shapes, it is to slow for quantitative determination the material is best observed as a suspension in non dissolving fluid. Saving is less useful technique at preformulation storage due to lack of bulk material. Andreason pipette is based on the rate difference of sedimentation of different particles, but techniques like this are seldom used due to their tedious nature instruments based on light scattering, (Royco), light blockage (HIAC) and blockage of electrical conductivity path (coulter counter) are used.
Surface Area Determination:Surface area is most commonly determined based on brunaver emette teller (BET) theory of adsorption. Most substances adsorb a mono molecular layer of gas under certain conditions of partial pressure of gas and temperature. Knowing the monolayer capacity of adsorbent and the area of absorbable molecule, the surface area can be calculated. the adsorption process is carried out with nitrogen at-195 degree Celsius at a partial pressure attainable when nitrogen is in a 30% temperature with an inert gas (helium).
The adsorption takes place by virtue of Vander wall’s forces. 2) POWDER FLOW PROPERTIES: When limited amounts of drugs are available Powder flow properties can be evaluated by measurements of bulk density, Carr’s index Hausner ratio and angle of repose. Changes in particles size and shape are generally very important an increase in crystal size or a more uniform shape will lead to a small angle of repose and a smaller Carr’s index. 5.
Bulk Density:Knowledge of absolute and bulk density of the drug substance is Very useful in Having some idea as to the size of final dosage form the density of solids also of affects their flow Properties Carr’s compressibility index can be used to predict the flow properties based on density measurement. Bulk density = Mass of the powder / Bulk volume Carr’s index (%) = Tapped density – Pored density *100 Tapped density A similar index has been defined by Hausner: Hausner ratio = Tapped density Pored density.
Angle of repose:The maximum angle which is formed between the surface of a pile of powder and horizontal surface is called the angle of repose. It is represented as ‘ ? ’ 6 Schematic representation of Angle of repose Where Tan ? = h/r ? = Tan -1 h/r h= Height of the pile r=Radius of the pile Relationship between flow, angle of repose, Carr’s index fee power flow 7 Flow Angle of repose Carr’s index ( % ) Excellent 40 23-35 Very Poor 33-38 Extremely Poor >40 Crystal Properties and Polymorphism:Many drug substances can exit in more than one crystalline from with different shape and lattice arrangements. This property is known as polymorphism.
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 from may be utilized to improve the rate and extent of bioavailability. For drugs prone to degradation in the solid state, physical form of the drug influences degradation. Selection of a polymorph that is chemically more stable is the solution in many cases.
Different polymorph also leads to different morphology, tensile strength and density of powder bed which all contribute to compression characteristics of materials. Some investigation of polymorphism and crystal habit of a drug substance as it relates to pharmaceutical processing is desirable during its Preformulation evaluation especially when the active ingredient is expected to constitute the bulk of the tablet mass. 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. Various techniques are available for the investigation of the solid state. These include microscopy (including hot stage microcopy), infrared spectrophotometer, single-crystal x-ray and x-ray powder diffraction, and thermal analysis. 8 Saturation Hygroscopicity: It is one of the important powder parameter that defines the stability of the material and it can be defined as the maximum moisture absorbance capacity of a drug powder from the atmosphere or the surroundings.
The method helps in determining moisture sensitivity of the drugs, Equilibrium Moisture Content (EMC) and also aids in selection of packing material for a finished dosage form. The experimental study is carried out by taking a known quantity of drug material in open trays and placed in desiccators, the samples are collected at regular intervals and moisture content or water content is analyzed by Karl-Fischer titration method. Melting Point: The melting point of a drug can be measured using three techniques :1) Capillary Melting 2) Hot Stage Microcopy 3) Differential scanning calorimeter or thermal Analysis.
Capillary Melting: Capillary melting gives information about the melting range but it is different to assign an accurate melting point. Hot Stage Microcopy: This the issued observation of melting under a microscope equipped with a heated and lagged sample stage. The heating rate is controllable and up to three transitions can be registered. Differential Scanning Calorimetry and thermal analysis: 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 9 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. pKa Determination:Determination of the dissociation constant for a drug capable of ionization within a pH rang of 1 to 10 is important since solubility and consequently absorption, can be altered by orders of magnitude with changing pH. The Henderson – Hasseslebach equation provides an estimate of the ionized and unionized drug concentration at a particular pH. For acidic compounds.
pH = pKa + log (un-ionized drug]) / [ionized drug]) II) SOLUABILITY CHARACTERISTICS OF THE DRUG: The solubility of a drug may be expressed in a number of ways. The U. S. Pharmacopia and national formulary lists the solubility of drugs as the number of milliliters of solvent in which 1gm of solute will dissolve. Solubility of drug is an important physicochemical property because it affects 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 lipophilic. The solubility of material is usually determined by the equilibrium solubility method, which employs a saturated solution of the material, obtained by stirring an excess of material in the solvent for a prolonged time until equilibrium is achieved :Common solvents used for solubility determination are:·Water , Polyethylene,Propylene Glycol ·Glycerin ,Sorbitol 10 ·Ethyl, Benzyle , Isopropyl Alcohol ·Methanol ·Tweens ·Polysorbates.
·Castor, Peanut, Sesame Oil ·Buffer at various pH Aqueous Solubility: The availability of a drug is always limited and the preformulation scientist may only have few quantities of drug material to analyze its characteristics, a very few quantity of drug is used to determine aqueous solubility, by dissolving known parts of drug in different parts of water. The Aqueous Solubility of drugs is characterized as follows Characterization of aqueous solubility of drugs S. no Parts of water Terms of solubility 1 Parts of drug 1 Less than 1 Very soluble 2 1 1-10 Freely soluble 3 1 10-30 Soluble 4 1 30-100.
Sparingly soluble 5 1 100-1000 Slightly soluble 6 1 1000-10000 Very slightly soluble 7 1 More than 10000 Practically insoluble Intrinsic Solubility (Co) :An increase in solubility in acid compared to aqueous solubility suggests a weak base and an increase in solubility in alkali suggests a weak acid. An increase in acidic and alkaline solubility suggests zwitter ion behavior. In this case there will be two pKa’s, one acidic & one basic. When the parity of the drug sample can be assured the solubility obtained in acid for a weak acid or alkali for a weak base can be assured to be the intrinsic solubility 11.
(Co. ) i. e. the fundamental solubility when completely unionized. The solubility should ideally be measured at two temperatures. 1) 4OC to ensure physical stability and the minimum density of water occurs at 4OC. This leads to a minimum aqueous solubility. 2)37OC to support biopharmaceutical evaluation. Partion coefficient: For series of compounds, the partition coefficient can provide an empiric handle in screening for some biologic properties. For drug delivery, the lipophilic/ hydrophilic balance has been shown to be a contributing factor for the rate and extent of drug absorption.
Although partition coefficient data alone does not provide understanding of in vivo absorption, it does provide a means of 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 partition coefficient much less than 1 are indicative of a hydrophilic drug.
Although it appears that the partition coefficient may be the best predictor of absorption rate, dissolution rate. Dissolution: The dissolution rate of the drug is only important when it is the rate limiting step in the absorption process. The rate of dissolution is directly proportional to solubility of the drug 12 Intrinsic Dissolution Rate: When dissolution is controlled solely by diffusion the rate of diffusion is directly proportional to the saturated concentration of the drug in solution under these conditions the rate constant K1 is defined by K1 = 0.
62 D2/3 v 1/6 w1/2 Where, V is the kinematic viscosity W is the angular velocity of a rotating disc of drug. Common Ion Effect: According to Le Chatelier principle presence of a common ion will shift the equilibrium from right to left and significantly reduces the solubility of a slightly soluble substances and any addition of solvent shift the equilibrium left to right and significantly increses the soluability.. Ex: AgCl (s) – Ag+(aq) + Cl- The ‘salting out’ results from the removal of water molecules as solvent owing to the competing hydration of other ions.
The reverse process ‘salting in’ arise with large anions e. g. benzoate, which open the water structure. These hydro topics increase the solubility of poorly water soluble compounds such as diazepam. IV) DRUG-EXCIPIENT COMPATIBILITY The success of formulating a dosage form depends upon careful selection of excipients that do not interact with drug or with each other this phenomenon can be investigated before the commencement of formulation by studying drug and various excipient mixtures. The knowledge of drug excipients interaction is useful for the formulation to select appropriate excipients.
The described preformulation screening of drug excipients interaction involves Geometric dilution of 5mg of drug in a 50% mixture with the excipients to maximize the likelihood of obscuring an interaction. Mixtures should be examined under nitrogen to ultimate oxidation and paralytic effect at a standard heating 13 rate on Differential Scanning Calorimeter (DSC), over a temperature range, which will encompass any thermal changes due to both the drug and appearance or disappearance of one or more peaks in thermograms of drug excipient mixtures are considered as an indication of interaction.
Preformulation testing provides a basic dossier on the compound and plays a significant role in identifying possible problems and suitable approaches to formulation. Such dossiers already exist for the common excipients. V) ANALYTICAL METHOD DEVELOPMENTS Analytical method development is one of the initial priorities in preformulation studies for detection of drug (main component), Intermediate compounds carried from synthesis and degradation products from chemical breakdown or instability.
Paradoxically, these latter contaminants are of greater importance because there quantification, identification and control affect the quality of drug batches. In addition chemical instability is more easily detected through an increased concentration of degradants than through decreased concentration of the main component. Methods are also required for quantification of other impurities such as residual solvents, catalyst residues and heavy metals and microbial contamination. Further analytical tests will also be specified such as general characteristics, colour, melting point, loss on drying and basic identification method.
Drug Assays are usually conducted using various analytical methods such as Spectrophotometers such as UV spectrophotometry or specific chromatography such as High Performance Liquid Chromatography (HPLC) or capillary electrophoresis. These techniques ensure that the drug is separated from impurities and breakdown products, all of which can then be quantified. Development of these methods allows specifications to be set for the required percentage of main component usually 98-101% by weight and limits for the tolerated levels of impurities. If required identification of impurities will also be conducted.
A reference sample will be retained and used as a standard for subsequent analysis. 14 VI) STABILITY STUDIES Preformulation stability studies are usually the first quantitative assessment of chemical stability of a new drug. These studies include both solution and solid state experiments under condition typical for the handling, formulation, storage, and administration of a drug candidate as well as stability in presence of other recipients. Factor effecting chemical stability critical in rational dosage form design include temperature, pH and dosage form diluents.
The method of sterilization of potential product will be largely dependent on the temperature stability of the drug. Drugs having decreased stability at elevated temperatures cannot be sterilized by autoclaving but must be sterilized by another means, e. g. , filtration. The effect of pH on drug stability is important in the development of both oral and parental dosage forms. Oral administration must be protected from the highly acidic environment of the stomach.
Buffer selection for potential dosage forms will be largely based on the stability characteristic of the drug such as – Solid state stability – Solution phase stability – Compatibility studies: stability in the Presence of excipients – Typical stability protocol for anew Chemical Entity Solid state stability:Chemical instability normally results from either of the following reaction: – hydrolysis, oxidation, and photolysis.
Esters and lactase and to lesser extent, amides are prone to solvolysis . Instauration or electron rich centre in the structure make the molecule vulnerable for free radical mediated or photo-catalyzed oxidation.
Amorphous materials are less stable than their crystalline forms. Denser materials are more stable to ambient stress. Elevated temperature studies:- 15 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 change is seen after 30 days at 60 degree centigrade, the stability prognosis is excellent.
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 on exposure light.
Though the extent of degradations small and limited to the exposed surface area, it presents an aesthetic problem. Exposure of drug to a 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 bye should be used in the formulation. 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. A shallow layer of drug exposed to a sufficient headspace volume ensures that the system is not oxygen limited. 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. 16
After completion of individual characteristics study the preformulation scientist By comparing the physicochemical properties of each drug candidate with in a therapeutic group, can assist the synthetic chemist to identify the optimum molecule, provide the biologist with suitable vehicles to elicit pharmacological response and advise the bulk chemist about the selection and production of the best salt with appropriate particle size and morphology for subsequent processing. After completion of the studies it is the responsibility of formulation scientist to develop a formulation by considering the required parameters. 17
DRUG INCOMPATIBILITIES Incompatibilities in pharmaceutical products are undesired physical, chemical or biopharmaceutical processes which take place during preparation, storage or administration resulting in decomposition of drugs and a failure to improve the patient’s condition. Incompatibilities may take place in a manner of drug-drug interactions or drug-additive and additive-additive interactions. Physicochemical conditions are the common factor causing incompatibilities. The most common physicochemical factors involving incompatibilities were reviewed as following: 1. Acid-Base Character 2. pH 3. Concentration 4. Oxidation 5.
Hydrolysis or Solvolysis 6. Temperature 7. Photolysis All incompatibilities may take place in a visual or hidden manner. Visual or visible incompatibilities usually result from inadequate solubility, viscosity changes, color change, turbidity, etc. The hidden incompatibilities which are not visible apparent may be difficult in detection. Pharmacists may encounter these incompatibilities, an understanding of physicochemical principles is useful for solving these problems. 18 DRUG INTERACTIONS Drug Interaction: Involves one drug which precipitates the change in the effect of other drug. Drug which precipitates the interaction – Precipitant.
Drug whose action is affected is called – Object Drug Diff. Causes: – Administration of two or more drugs simultaneously – Patients may visit many doctors – Concurrent use of prescribed & non – prescribed drugs – Patient non-compliance Types of Drug Interactions: Beneficial Drug Interactions: Ex: Improved Compliance- Anti TB agents, Ferrous Sulphate & Folic Acid Ease of administration- Triple Vaccine (Diphtheria, Pertusis, Tetanus) Synergistic effect – Trimethorphan + Sulfamethoxazole Aspirin + Codeine Decreased adverse effects – Levodopa + Carbidopa Adverse Drug Interactions: Undesirable / Unintentional Hetergic (Antagonism).
– When two drugs produce diff. effects Homergic (Synergistic) – when two drugs produce similar effects 19 Mechanisms: § Pharmaceutical § Pharmacokinetic § Pharmacodynamic 1) Pharmaceutical: Even before administration Ex: Noradrenaline, tetracyclines, corticosteroids – Electrolytes 2) Pharmacokinetic Drug Interactions: Interference with absorption Changes in protein Binding Modification of drug metabolism Interference with renal excretion 3) Pharmacodynamic Interactions. Modification of drug at receptor sites. Disturbance of water & electrolyte balance. 20 PHARMACEUTICAL FORMULATION ADDITIVES Formulation Bulk Drugs Active.
In active (Excepients) Active Ingredients Soluble Drugs – Systemic Effect Insoluble Drugs – local effect Any formulation or design may be described as the process whereby the formulator insures that the correct amount of drug in the right form is delivered at or over proper time at the proper rate and in the desired location, while having its chemical integrity protected to that point. Excepients: – to produce satisfactory drug release – to active acceptable physical & mechanical properties – to facilitate the manufacture Cubic: If the drug contains proper Crystalline Structure Non cubic: Direct compression Cubic Structure:
21 Structure is same along each axis, so no alignment is necessary between individual particles. Ex: NaCl Non Cubic: Some realignment is necessary which results in a reduced probability of bonding. So addition of Excepients, Compaction of crystals depends on Particle size distribution, crystal shape, bulk density & moisture content. Compression: Crystals are fractured & the fragments form a close – packed arrangement, which readily consolidates on compression. Formulation Development: Bioavailability Consideration: Availability of Drug in different formulations: – Solution – Suspension – Micronised drug in capsule form.
– uncoated tablets – Coated Tablets Non Active Ingredients: They fall under 6 categories: – Diluents – Binders – Lubricants – Disintegrants – Colors – Sweeteners (flavors) By Function: 2 categories Those effects compress ional characteristics. Viz. , Diluents, Binders & Adhesives, Lubricants, Anti adherents, Glidants 22 Those which effect biopharmaceutics, Chemical & Physical stability and Marketing Considerations. Viz. , Disintegrants, colors, Flavors & Sweeteners and other miscellaneous components like Buffers, Adsorbents etc. Diluents: (Fillers) – Small Dosage formulations. Bound Ex: CaSO4. 2H2O – Moisture 12% moisture, hygroscopic.
Unbound For Chewable Tablets – taste & mouth Feel Diluents Ex: Lactose, Starch, MCC etc. Lactose: Has good drug release rates. Disadvantages: it may discolor in the presence of amine drug Bases or Salts & alkaline Lubricants. Starch: (Corn, Wheat / Potatoes) Moisture: 11-14% Dried Starch: 2 – 4 % It serves as local desiccant by localizing the moisture in moisture sensitivity drugs. Directly Compressible Starch: (Physically Corn Starch) Diluent, Binder, Disintegrant agent. Mannitol: For Chewable tablets, Mouth Feel is due to negative heat of solution & its slow solubility with cool sensation during dissolution of sugar.
72% as sweet as sucrose Non Hygroscopic – Best diluent in Vitamin Preparations 23 MCC: Hardness, Friability and Disintegrant. Binders & Adhesives: Water Soluble / Dispersible Binders Water Insoluble Binders – PVP, MC, Na CMC, HPMC • To add cohesiveness to powders • Granules tend to entrap less air than powders when compressed. Criterion to choose a binder is – Its compactability – It must impart sufficient cohesion to powders, to allow normal processing; (Sizing, Lubrication, Compression & Packaging) yet allow tablet to disintegrate & the drug to dissolve.
Ex: Acacia, Tragacanth, Sucrose, Gelatin, Starch, Cellulose – MC. Na CMC. Etc. , Disintegrants: they facilitate the Break-up – Can be added during granulation (Intragranulation) / In Lubrication (extra Granulation) If Intragranular – they cause much finer dispersion Disadvantage : they impede tablet wetting, disintegration & Dissolution. – The effectiveness of many Disintegrants is affected by their position with in the tablet – Some possess binder / adhesive properties. 24 Adding Lubricants and Disintegrants at Blending Stage is termed as – RUNNING POWDER Ex: Starch, Celluloses, MCC.
MCC: (as low as)10% – good disintegrant. – allows the water to enter the tablet matrix by means of capillary pores, which breaks the hydrogen bonding b/n adjacent bundles of cellulose micro crystals Disadvantage: – Excessive levels – sticking to tongue, due to rapid capillary absorption, dehydrating the moist surface & causing adhesion. Lubricants, Anti adherents & Glidants: Lubricant: reduce friction b/n the granulation & die wall during compression & ejection. Anti Adherent: prevent sticking to the punch & to a lesser extent, the die wall. Glidant: improve flow characteristics of the granulation.
Lubricants: Classified as Water soluble – effervescent (Boric acid, Na Benzoate, NaCl, SLS) Water insoluble – more effective & useful at lower concentrations. Function by two mechanisms: Fluid (or hydrodynamic) lubrication Boundary Lubrication 25 Fluid Lubrication: The two moving surfaces are viewed as being separated by a finite & continuous layer of fluid lubricant. Ex: Mineral oils. Boundary Lubrication: Adherence of polar portions of molecules with long carbon chains to the metal surfaces of the die wall The adherence is more than fluid type. Ex: Mg. Stearate Different aspects of Lubricants : 1.
Lubricants tend to equalize the pressure distribution in a compressed tablet. 2. They increase the density of the particle bed prior to compression. 3. If lubricants are added to granulation, they form a coat around the individual particles which remain more or less intact during compression. This effect may extend to tablet surface. 4. Best lubricants are HYDROPHOBIC, they effect the disintegration time. (So add a less hydrophobic ingredient along with the Lubricant. ) The mixture of Lubricant and a hydrophilic agent (Disintegrant) is called as RUNNING POWDER. Ex: Starch / Lubricant – 1:1, 1:4. 1.
As the particle size decreases, formula requires more quantity of lubricant. (NMT 1% is best conc. ) 2. Lubricants should be of fine size as they tend to function by coating so they are effected by their surface area & extent of particle size reduction. 3. Length of mixing with lubricant also effects disintegration – dissolution. Lubricants should not be added in granulation because they are expected to exert action on granules. If used they decrease the binding efficiency. 26 Problems due to lack of proper Lubrication: – Lack of adequate lubrication leads to Binding machine strain – Excessive binding leads to cracked & fragmented tabs at ejection.
– Damage to lower Punch heads. Sticking: Dull tab faces Early stages of sticking Filming to punch faces (This occurs when punches are improperly cleaned or polished / when tabs are compressed in a high humidity / when lubrication is inadequate. ) Advanced state of sticking is Picking ( When portions of the tablet faces are lifted or picked out & adhere to punch faces. ) Reasons for Sticking – Results from improperly dried granulation, from punches with incorrectly designed logos Capping & Laminating: From inadequate glidant use associated with proper bonding or with over lubrication. Antiadherants: Used mainly in formulas whic.