Pharmaceutical Excipients One

What are excipients? are the chemical components of medicine other than the active ingredient. - classified as their function in dosage formulations. What are some roles of excipients? - modifying solubility and bioavailability of the API - enhancing stability of the API - helping active ingredients maintain a preferred polymorphic form or conformation - maintaining pH and osmolarity of liquid formulations - acting as antioxidants, emulsifying agents, aerosol propellants, tablet binders, and tablet disintegrators - preventing aggression or dissociation - modulating the immunogenic response to active ingredients. What does the excipient affect? The biological, chemical and physical properties of the drug product are directly affected by the excipients chosen, their concentration and interactions with the API: 1) Consistency of drug release and bioavailability 2) Stability including protection from degradation 3) Ease of administration Excipients are sub-divided into various functional classifications depending on the role they play in the formulation. eg lactulose. Excipients and their functional classes a diluent, filler or bulking agent in tablets and capsules. A carrier for dry powder inhalation products. Excipients can have different grades, 1/7 types and sources depending on those different functional role. Different grades of lactose are commercially available that have different physical properties. This allows for a selection to be make based on the particular need for example during tablet development. Tablet Excipient: Lactulose 1) Wet granulation: usually, finer grades of lactulose are utilised as the binder is utilised more efficiently and this permits better mixing and granule quality. 2) Direct compression: in contrast here, spray dried lactose is used as it flows better and is more compressible. - diluent (fillers) eg lactose, microcrystalline cellulose - disintegrants eg sodium starch glycoWhat are the key excipients in a tablet? late, croscarmellose sodium - binders eg PVP, HPMC - lubricants eg magnesium stearate - glidants eg colloidal SiO2. Tablet Diluents (Fillers) 1) Bulking agent: to make a tablet weight practical for the patient: minimum tablet weight is typically - 50mg 2) Compression aid: deforms and/or fragments readily to facilitate robust bonding in tablet compacts eg microcrystalline cellulose 3) Good bulk powder flow- diluents have a strong influence: good flow of bulk powders is very important in designing a robust commercial tablet product. Lactose most common filler in tablets. It possesses a series of good filler properties: dissolves readily in water, has a pleasant taste, is non hydroscopic, is fairly non reactive, shows good compatibility. 2/7 Main limitation is that some people are intolerant to lactose. Disintegrants - starch - as an aid to de-aggregation of compacted tablets. - cause rapid break up (disintegration) of the tablet compact upon exposure to moisture - dissolution occurs simultaneously with disintegration. What are the three major mechanisms and factors affecting tablet disintegration? 1) Swelling 2) Porosity and Capillary Action (Wicking) 3) Deformation Swelling although not all effective disintegrants swell in the contact with water, by swelling in contact with water the adhesiveness of other ingredients in a tablet is overcome causing the tablet to fall apart. Swelling is believed to be a mechanism in which certain disintegrating agents (such as starch) impart the disintegrating effect. the disintegrant particles (with low cohesiveness and compressibility) themselves act to enhance porosity and provide pathways into the tablet. Liquid is Porosity and Capillary Action (Wicking) drawn up or "wicked" into these pathways through capillary action and rupture the inter particulate bonds causing the tablet to break apart. 3/7 Deformation Starch grains are generally thought to be "elastic" in nature. But, with the compression forces involved in tableting, these grains are believed to be deformed more permanently and are said to be "energy rich" with this energy being released upon exposure to water. In other words, the ability for starch to swell is higher in "energy rich" starch grains than it is for starch grains that have not been deformed under pressure. SLIDE 18 AND 19 Super Disintegrants What are some advantages and disadvantages of super integrants? Tablet Binders Three major groups of compounds have been developed which swell to many times their original size when placed in water while producing minimal viscosity effects. These include: modified starches, cross-linked polyvinylpyrrolidone, modified cellulose. Advantages: - effective in lower concentrations than starch - less effect on compressibility and flow ability - more effective intragranularly. Disadvantages: - more hydroscopic (may be a problem with moisture sensitive drugs) - some are anionic and may cause some slight in-vitro binding with cationic drugs (not a problem in vivo). act as an adhesive to 'bond together' powders, granules and tablets to result in the necessary mechanical strength. 4/7 Example formulations using binders WATER - as a powder with other excipients in dry granulation (roller, compaction, slugging) or as an extra-granular excipient in a wet granulation formulation - as a powder with other excipients in wet granulation. When the granulating fluid is added, the binder may dissolve partially or completely to then exhibit adhesive binding properties. - most commonly the binder is added already dissolved in the granulating fluid to enable more rapid and, more effective granulation. MAGNESIUM STEARATE - Lubricant prevent adherence of granule/powder to punch die/faces and promote smooth ejection from the die after compaction. Tableting lubricants Lubricants tend to be hydrophobic, so their levels (typically 0.3-2%) need to be optimised: - under-lubricated blends tend to flow poorly and show compression sticking problems - over-lubricated blends can adversely affect tablet hardness and dissolution rate 1) True Lubricant Role: to decrease friction at the interface between a tablets surface and the die wall during ejection and reduce wear on punches and dies. What are the three roles of lubricants? 2) Anti-adherent role: prevent sticking to punch faces or in the case of encapsulation, lubricants prevent sticking to machine dosators, tamping pins 5/7 3) Glidant role: enhance product flow by reducing inter particulate friction. - low shear strength: want the lubricant to hear during blending, not the granules or other excipients in the formulation - able to form a "durable layer" over the surface covered. What are properties of a good lubricant? - non-toxic - chemically inert - unaffected by process variables - posses minimal adverse effects on the finished dosage form. What are the two major types of lubricants? 1) Hydrophilic: generally poor lubricants, no glidant or anti-adherent properties. 2) Hyrdophobic: most widely used lubricants in use today are of the hydrophobic category. Hydrophobic lubricants are generally good lubricants and are usually effective at relatively low concentrations. Many also have both anti-adherent and glidant properties. For these reasons, hydrophobic lubricants are used much more frequently than hydrophilic compounds. Magnesium Stearate: Lubricant - if concentrations are too low, or distribution and mixing times are inadequate, problems can arise, such as punch filming, picking, sticking, capping, binding in the die cavity - if concentration are too high, or distribution and mixing times are too great, potential problems include: decrease in tablet hardness, inability to to compress into tablets, increase in tablet disintegration times (DT's), decrease in rate of dissolution. 6/7 Chemical composition of Magnesium Stearate - exists as "plate-like" crystals (or lamellae) stacked together like a deck of cards - as the blending process proceeds, plates continue to shear off and coat adjacent particles of granules, drug or other excipients - the higher the concentration of Magnesium Stearate used or the longer this blending continues, the more complete this coating of the adjacent particles will become - for effective lubrication you do not want to coat everything too completely with the lubricant or the problems mentioned previously are likely to occur. SLIDE 32 AND 33 Tablet Glidants COLLOIDAL SILICON DIOXIDE (TALC) - good bulk powder flowability is especially important during high speed processing. - 7/7