Industrial Pharmacy PDF

Lec. 1 Industrial Pharmacy Dr. Ali Saeed Aljaberi References: The Theory and Practice of Industrial Pharmacy by L. Lachman Tablets - The tablet is a solid dosage form containing one or more drugs (active pharmaceutical ingredients) as well as...

Lec. 1 Industrial Pharmacy Dr. Ali Saeed Aljaberi References: The Theory and Practice of Industrial Pharmacy by L. Lachman Tablets - The tablet is a solid dosage form containing one or more drugs (active pharmaceutical ingredients) as well as other substances (excipients = additives = adjuvants = adjuncts). - They are used mainly for systemic drug delivery (i.e. swallowed whole, chewed, or dissolved or dispersed in water before being administered), and may be used for local drug delivery (i.e. on a mucous membrane). - It is estimated that at least 90% of all drugs used to produce systemic effect are administered by the oral route. Manufactured by: 1- Compression for powder of low cohesive force the majority. 2- Or molding for powder of some cohesive force: The powder is moistened with a liquid then the moist mass pressed into the mold opening till the liquid evaporate then the tablets are removed. 3- Freeze drying (sometimes referred to as oral lyophilizates). 4- Extrusion The additives are added to improve the quality of the drug. But it is better to optimize their use (i.e. the fewer additives is more better) because they may have side effects or interact with the drug or with each other. Also, the amount of the additives should be minimum as possible (ex: super disintegrants are use as they promote disintegration with very small amount). 1 Lec. 1 Industrial Pharmacy Dr. Ali Saeed Aljaberi Also, the amount of the drug must be optimized to maintain the efficacy and decrease the side effect of drugs that are administered orally, solid oral dosage forms (tablet and capsule) represent the preferred products. ❖ Tablets and capsules are more preferred than liquid dosed forms (syrup, suspension, emulsion and elixir) because the latter suffer from the following disadvantages: 1) The patient is asked to measure his medication by a spoon. Such dose measurements are in error by a factor may reaches up to 20-50%. 2) Liquid dosed forms are more expensive to ship. 3) They are susceptible to breakage and leakage during shipment. 4) Taste-masking is more difficult in liquid dosed forms. 5) They are less stable physically, chemically and biologically. ❖ There are basically three reasons for having liquid dosage forms of a drug: 1) The liquid form is what the public has come to expect for certain types of products (e.g., cough medicines). 2) The product is more effective in a liquid form (e.g., many adsorbents and antacids). 3) The drug(s) are used fairly commonly by young children or the elderly, who have trouble swallowing the solid oral dosage forms. Advantages: 1. Tablets are accurate and unit dosing. 2. Lowest cost of all dosage forms. 3. Tablets are the easiest in term of handling, packaging, and shipping. 4. Product identification is potentially the simplest and cheapest. 2 Lec. 1 Industrial Pharmacy Dr. Ali Saeed Aljaberi 5. They may be used for special release profile such as delayed-release and enteric coated products. 6. Large-scale production is easier. 7. More stable than liquid dosage form. Stability of solid dosage forms as tablets (because there is no water) > Suspension (because the majority of drug is suspended in water) > Solution (because all the drug is dissolved in water) 8. More safe than injections (over dose in IV injections will cause problems). 9. Prepared in different ways. Disadvantages: 1. Some drugs resist compression (poor compressibility) resulting in friable tablets owing to their amorphous nature or low density. 2. Drugs with poor wettability, slow dissolution rate, and large doses are difficult to be formulated as tablets. 3. Drugs with bitter taste (intolerable), objectionable odor, or sensitive to air or moisture are better to be formulated as capsule or as coated tablets. 4. Unsuitable for very young patients as it may be difficult to swallow. 3 Lec. 1 Industrial Pharmacy Dr. Ali Saeed Aljaberi Classification of tablets A- Based on drug release characteristics 1. immediate release tablets Rapid drug release, rapid onset. Short duration of action so that frequent dosing is required which will decrease the patient compliance, there is fluctuation in blood concentration. 2. Modified release (MR) tablets (sustained (SR), extended (ER), prolong or long acting (LA)) Slow drug release with nearly constant rate, differ in the formulation (i.e. types of additives), slow onset, long duration of action, and nearly consistent blood concentration. Modified release 3. Delayed release tablets Delayed drug release (i.e. the release doesn’t occur unless the tablet reach certain site), after this period the release become mostly immediate or sometime modified. Ex: enteric coated tablets in which the drug released in the lower part of the intestine (as in NSAID because they irritate the gastric wall). 4 Lec. 1 Industrial Pharmacy Dr. Ali Saeed Aljaberi 4. Controlled release (CR) tablets The release is slower with constant rate (i.e. zero order release). If the amount of the drug released is plotted against the time, straight line obtained Slow onset of action, very long duration of action, consistent blood concentration. Ex: transdermal therapeutic system (patches) 5. Multilayered (XL) tablets The release of drug is rapid with nearly constant rate. The tablet made of 2 layers: a- The outer layer formulated so that it will release the drug as an immediate release tablet. b- The inner layer formulated so that it will release the drug as a modified release tablet. 5 Lec. 1 Industrial Pharmacy Dr. Ali Saeed Aljaberi MSC 1st tab. % Released 2nd tab. Time (hr) Also the capsule can be made with rapid onset and long duration and nearly consistent blood concentration - Part of the powder left without treatment to release the drug immediately rapid onset. - Part of the powder is treated by coating to release the drug slowly long duration and nearly consistent blood concentration. This type of capsules called spansules. 6  Lec. 1 Industrial Pharmacy Dr. Ali Saeed Aljaberi B- Formulation ingredients (excipients) or site of administration Type Def. Excipients Character , Adv. & diadv. 1-Disintegrating Swallowed , disintegrate, release All the Disadv: tablets the drug for dissolution excipients 1- Slow onset as the disintegration process takes time (not suitable for the (conventional including the angina patient because he need rapid onset) tablets) disinigrant 2- Difficulty in swallowing 2- Chewable tablets Mechanically disintegrated in the All the Adv. mouth by chewing into fragments, excipients 1- More rapid onset then swallowed, then the drug except the 2- Easy in swallowing (easy in administration) dissolves in the GIT fluids, not in disintigrant Ex:Antacid, Vitamins, Aspirin the mouth (i.e. the drug absorbed from the GIT not from the mouth) 3-Effervescent tablets - Dropped into glass of water All the Adv. Chemical reaction between excipients 1- More rapid onset carbonate or bicarbonate salt and except the 2- Easy in swallowing (easy in administration) organic acid as citric acid or disintegrant 3- The production of CO2 gas will: tartaric acid which lead to a- Mask the metallic or bitter taste of the drug liberation of carbon dioxide b- The effervescence physiologically produce patient compliance. Dissolution. - Organic acid are used not mineral acids because they are strong acids - The solution administered during which are corrosive. effervescent. - Slight excess organic acids are added because they have a palatable taste. - Effervescent tablets must be packaged protected from moisture because the moisture will initiate the reaction between some molecules and the reaction will produce water which will initiate the reaction between the remaining molecules the tablets will become as a paste. 7  Lec. 1 Industrial Pharmacy Dr. Ali Saeed Aljaberi 4-lozenges Dissolve slowly in the mouth All the Used for local effect in the mouth or throat (ex: local anesthetic, antiseptic & excipients antibiotics) except the disintigrant 5-sublingual and Dissolve in the mouth or under the All the - used for systemic effect buccal tablets tongue and the drug absorbed excipients Adv. from the mouth except the 1- More rapid onset as the region under the tongue is highly vascular disintigrant rapid absorption (ex: nitroglycerin tablets). 2- Easy in administration. 3- Bypass the first pass effect (as in case of progesterone, levodopa, and propranolol – 90 to 95% of them metabolized in the liver-). Characters of the tablets: 1- It should be porous. 2- It should be small (drugs with large doses cannot be made as sublingual tablets). 3- The drug and the excipients must be water soluble. 6-Tablets for solution Dissolved in water and All the Adv. or soluble tablets administered as solution excipients 1- More rapid onset except the 2- Easy in swallowing (easy in administration) disintegrant 3- Avoid preparing the drug as liquid dosage form which may lead to a stability problem. 4- Decrease the local irritation of some drugs (ex: NSAIDs) on the gastric mucosa. 7-Compressed Vaginal suppositories prepared by - Have higher stability than ordinary vaginal suppositories. suppositories or compression (ex: Metronidazole - They are for vaginal use not for rectal use because the vagina contains inserts or pessaries tablets) enough fluid that promote disintegration. 8  Lec. 1 Industrial Pharmacy Dr. Ali Saeed Aljaberi 8- Orodispersible Disintegrate and/or dissolve rapidly All the Adv.: tablets in the month (either on or beneath excipients with 1- Increase patient compliance the tongue or in the buccal cavity) super 2- Ease of swallowing for both children & elderly without water within few seconds to disintegrant 3- Fasting onset of action. few minutes, liberates its components as a solution or suspension, which in turn can be swallowed easily without water. It can also be swallowed intact by using water to push them down to the stomach. 9- Implantation Are inserted subcutaneously to Disadv.: tablets provide very long and constant 1- The need for surgical operation to apply and discontinue the therapy. release period ranging from one 2. Tissue toxicity at the site of implantation. mouth to one year. These tablets are usually cylindrical, small in size and do not exceed 8 mm in.diameter 9  Lec. 1 Industrial Pharmacy Dr. Ali Saeed Aljaberi C. According to coating: Type Def.: Role of coat 1- Sugar coating - The tablet is coated by aqueous solution of sugar (i.e. syrup if 1- Masking the unpleasant taste or bad color of the drug (ex: the drug is stable in water). paracetamol tablets are coated because one of its - Cannot be used if the drug is unstable in water. degradative products has a brown color) - The coat has shiny appearance. 2- Protection from moisture (hydrolysis) & light (photolysis) - Edges of tablets are not sharp but curved. & oxidation ( ex: furosemide is sensitive to light) - Thick coat cause increase in weight by more than 50%. - Some companies produce a non-coated tablets and - The coat cannot be engraved or printed by a letter because the packaged in a green strips. sugar coat has many layers. - Other companies produce coated tablets and packaged in transparent strips. 3- Slow down the drug release to obtain modified release tablets 2- Film coated - The tablets is coated by: - The same role tablets a- Aqueous solution of water soluble polymer (if the drug is stable in - Adv.: decrease time required for coating lower coast water). b- Non aqueous solution (if the drug is unstable in water) - The coat has non shiny appearance. - Edge of the tablet are sharp. - Thin coat cause small increase in weight (2-4%). - The coat can be engraved or printed by a letter. 3- Enteric coated the tablet coated by substances resist dissolution in gastric fluids but Used for: dissolved in intestinal fluids 1- To obtain delayed release. 2- For drugs that are deactivated in stomach or irritate the gastric wall - Engraved or printed tablet may be uncoated or film coated (i.e. cannot be sugar coated) 10  Lec. 1 Industrial Pharmacy Dr. Ali Saeed Aljaberi D. According to method of preparation: 1- Molded tablet or tablets triturates. 2- Compressed tablets a- single layer b- multilayered (XL tablets) 11 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi Desirable properties of raw materials 1- Particle size affect: a- Segregation: separation of powder mixture due to variation in particle size. - Segregation of powder inside tablet machine lead to no uniform filling of the die and no uniform compression. - To decrease tendency for segregation, particles should have narrow size range & similar shape. - It is impossible to obtain particles with the same size but particles of narrow size range can be obtained by size reduction of large particles by grinding or size enlargement of small particles by granulation or both. b- Flowability - Enhanced by using regular spherical particles – with smooth surface- narrow size ranger- optimum fines (i.e. fine particles) – decreased contact points between particles to avoid aggregates. - Bad flowability inside tablet machine will lead to irregular tablets. - If particles have irregular surface (with grooves on the surface) lubricant used which adhere to the surface of particles, filling the grooves regular spherical particles enhance flowability. - The lubricant itself has a bad flowability to adhere to the surface of particles. - But excess lubricant will fill spaces between particles bad flowability. 2- Crystalline form - Solid may exist as: a- Anhydrous form (amorphous) do not contain water of crystallization. b- Hydrous form (crystalline) contain water of crystallization. - The hydrous form is more sensitive to climatic changes (i.e. temperature change). - Some drugs exhibit polymorphism or have different crystal habit have different dissolution rate and bioavailability. Ex: hydrous lactose (filler), is more sensitive to temperature changes than anhydrous lactose. 3- Variability There are differences in quality between different sources and different lots of additives (ex: effectiveness of Mg stearate as a lubricant differ depending on the source). 4- Moisture content - Benefit of moisture: low moisture content is desirable to act as a binder - The moisture content must be optimum - Higher moisture content is undesirable. 1 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi 5- Purity Highly pure raw material is required Ex: - Small % of acetylsalicylic anhydride impurity decrease dissolution rate of aspirin itself. - Microbial contamination may harm the patient. 6- Compatibility Drug-Drug & Drug-Excipient interactions should be avoided Tablet properties 1- A tablet should be an elegant product having its own identity while being free of defects such as chips, cracks, discoloration, contamination, and the like 2- Should have the strength to withstand the rigors of mechanical shocks encountered in its production, packaging, shipping, and dispensing 3- Should have the chemical and physical stability to maintain its physical attributes over time. 4- Must be able to release the medicinal agent(s) in the body in a predictable and reproducible manner 5- Must have a suitable chemical stability over time so as not to allow alteration of the medicinal agent(s). Tablet ingredients (formulation) 1- Active ingredient The dose of the drug affect the design and formulation of the tablets: a- Content uniformity b- Drug stability c- Other physical properties 2- Additives and excipients Added to improve the quality of the drug and classified into: a- Those which impart satisfactory processing and compression characters to the formulation. b- Those which help to give additional desirable physical characters to the tablets.  There are 3 important aspects for each additives: Its type, its concentration, and its method of addition 2 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi Tablet ingredients Additives and Active ingredient excipients Those which impart satisfactory processing and Those which help to give compression characters to additional desirable the formulation physical characters to the tablets Diluents 1- Lactose disintegrant 2- Other sugars or sugar alcohol 3- Inorganic substances colors Binders (ex: cellulose) Glidents flavors Lubricants sweetening agents polymers or waxes 3 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi Factors to be considered when we choose the additives: - No ideal additives each type has advantages and disadvantages - The type and the concentration of additives are very important. - The side effects of the additives must be considered (no chemical substance is completely safe) - The number of the additives and the concentration of each additives should be minimum. - Additives that are effective in low concentration are preferred while additives that are effective in high concentration should be modified to be effective in lower concentration. - The method of adding the additives is very important: some additives are added as a dry powder, others to be uniformly distributed they are added as a solution (aqueous or non-aqueous) Excipients are necessary for the following reasons: 1- Some drugs have small doses that cannot be compressed alone, e.g., thyroxin 0.025 mg. 2- Some drugs have poor compressibility that cannot be compressed alone. 3- If the tablets compressed alone, they will not disintegrate or disintegrate very slowly. A.Diluents (Fillers) Diluents are materials used to make up the required bulk of the tablet when the drug itself is inadequate to provide this bulk. - Tablets weight must be at least 50 mg so, in case of highly potent drugs (dose is very small) and the tablet weight will be less than 50 mg filler added to increase the bulk volume. - But if the dose of the drug is large and the tablet weight is higher than 50 mg filler may: not added or added if it has another role in slowing the release or improving the dissolution of the drug or act as a binders or disintegrants. 4 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi Requirements of ideal fillers 1- Relatively chemically inert 2- Non hygroscopic 3- Biocompatible (i.e. in vivo compatible) 4- Water soluble or at least hydrophilic (sometimes water insoluble filler is needed to slow the release of the drug) 5- Good compatibility 6- Acceptable taste 7- Cheap Examples: A. Organic substances 1- Sugars i- Lactose (most used) Advantages 1- Water soluble 2- Pleasant taste 3- Non hygroscopic 4- Fairly non- reactive 5- Good compatibility Disadvantages Some people have intolerance to lactose (due to deficiency in lactase enzyme) GIT disturbance Forms: 1- α-lactose monohydrate most used in wet granulation with poor flowability, and it has low cost. It contain approximately 5% moisture which 5 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi consider potential source of instability with moisture sensitive drugs. Usually unreactive, except discoloration when combined with amine and alkali (maillard reaction). It has no effect on drug release rate. 2- Anhydrous (amorphous): Adv.: a- Used in direct compression as low moisture content is required. b- Not sensitive to temperature changes. c- It does not undergo discoloration (brown discoloration) with amines and alkali compounds. d- Inexpensive. Disadv.: 1- It doesn’t exhibit free flowability. 2- Pick up moisture at elevated humidity changing tablet dimension. 3- Spray dried lactose is used as directly compressible vehicle because of free flowability. Its compressibility is adversely affected if dried bellow 3% moisture. It is more prone to darkening in presence of excess moisture, amine due to furaldehyde, Usually neutral or acidic lubricant should be used. In general, all lactose types show: 1- Good drug release. 2- Its granulations are easily dried. 3- The disintegration time of lactose containing tablets are not very sensitive to variation in tablet hardness. 4- Low cost. 6 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi Other sugars or sugar alcohol 1- Sugars: as glucose , sucrose and dextrose Dextrose (hydrous and anhydrous) is sometimes used in the formulas to replace some of lactose to minimize the discoloration (when used with alkaline compounds). 2- Sugar alcohols: as sorbitol & mannitol - Mannitol has –ve heat of solution, so, gives cooling sensation when sucked or chewed used in lozenges & chewable tablets. It is non hygroscopic, expensive, has poor flow and required high lubricant level. 2- Polysaccharides a- Starch (used as diluent, binder or disintegrant) It may be derived from different sources such as corn, wheat or potatoes. - It is used as diluent in the ratio of 50-60%, added in the dry form at the beginning of the procedure (mixing step). - Binder in the ratio of 10-20%, used as paste in the preparation of wet mass step. - Disintegrant in the ratio of 5-20%, added finally after granulation (to allow rapid water uptake, swelling and destruction of the tablet). - Sta-Rx® 1500 is directly compressible, freely flowable, and self-lubricant. - Celutab and Emedex (dextrose + maltose) Is used in chewable tablets because of sweetness and smooth mouth feel As an alternative to mannitol. b- Celluloses ( used also as binder & disintegrant) Adv.: 1- Chemically inert 2- Biocompatible 3- Used also as dry binders and disintegrants 4- Compatible with many drugs 7 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi Disadv.: Hygroscopic Example: Powdered cellulose - Consist of finely divided amorphous and crystalline α-cellulose particles. - May be used alone or together with other fillers. - Has poor compressibility and poor flow properties. - Has poor binding properties and low dilution potential. - It is water insoluble. - It is inexpensive. - Possess some degree of inherent lubricity. Microcrystalline cellulose (MCC) (Avicel) - Prepared by hydrolysis of cellulose then spray drying Adv.: 1- Used in direct compression 2- Used in wet granulation (5 – 15%) to minimize hardening of the tablets & reduce mottling (dye migration) after drying. 3- Different particle sizes can be prepared with different flowability. 4- Hard tablet, at low pressure are usually obtained when MCC is used. 5- They are biocompatible, chemically inert and they have good tablet forming and disintegration property. Disadv.: 1- It undergo plastic deformation on compression, it is more sensitive to lubricants. 2- Fair flowability. 8 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi B. Inorganic substance Calcium phosphate dibasic anhydrate Adv.: 1- Good flowability 2- Hard tablet produced 3- Used in wet granulation and direct compression 4- inexpensive Disadv.: 1- Water insoluble but hydrophilic (i.e. easily wetted by water) used to slow the release of the drug. 2- Slightly alkaline, so, must not be used if the drug is sensitive to pH above of 7. 3- Ca++ form insoluble complex with some antibiotics as tetracycline. 4- They are abrasive in nature and hence cause wear of tablet tooling. 5- High bulk density than organic filler. They are used extensively in vitamins and mineral preparations. - Trade name: Emcompress, A-TAB - Trade name of anhydrous dicalcium phosphate: A-TAB (cannot be used for direct compression because it contain water) C. Co-processed excipients Are a combination of two or more excipients designed to physically modify their properties in a manner not achievable by simple physical mixing and with significant chemical change. These excipients have high functionalities as compared to individual excipients like better flowability, compressibility, reduced lubricant sensitivity. 9 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi Selection of diluents 1- Its properties (compatibility, flowability, solubility, disintegration qualities, hygroscopicity, lubricity, and stability) 2- Experience of manufacturer 3- Cost B- Binders They are substances that bind the particles together to form granules (in wet and dry granulation) or to promote the formation of cohesive compacts (in D.C). - Too much binder or too strong binder make hard tablet. - Too few binder or too weak binder make friable tablet. Adding: 1- The first choice is using the binder as a solution it will be more effective specially if there is low cohesive properties of tablet ingredients: used as granulating liquid in wet granulation - Their solution are highly viscous. - Aqueous solution are used (safer), but if the drug is moisture sensitive they can’t be used non aqueous solutions are used for moisture sensitive drugs. 2- The second choice is using the powder in dry powder if there are problems in using it as solution and specially if there is some cohesive properties of the tablets ingredients. - Mixed with dry powder before granulation. - Mixed with granules before compression. 10 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi Examples: 1- Starch paste: concentration 10-20%. It is prepared by dispersing starch into water which is then heated for certain time. A properly made paste is translucent rather than clear. 2- Acacia and tragacanth: are natural gums. These materials are more effective as solution (10-25%) than if they are used as powders. Disadv.: a- They differ in composition and performance according to their origin. b- Easily contaminated by bacteria. 3- Gelatin solution: concentration 10-20% water used as aqueous solution. Bacterial growth is a troublesome. 4- Liquid sugars: such as liquid glucose (50%) or liquid sucrose (50-74%) may be used. They are cheap. Disadv.: a- They produce brittle compacts b- Bacterial growth is possible. 5- Modified natural polymers  Cellulose solutions: there are many types of cellulose, some of them are water soluble and others are water insoluble can be used as aqueous or non-aqueous solutions. - Hydroxyl propyl methyl cellulose (HPMC) water soluble used as aqueous solution: very effective so it is the best to decrease the incidence of capping. - MCC it is used for tablets that are compressed with very high pressure to avoid the formation of very hard tablet. It can be used in both wet-granulation & direct compression. 11 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi - Ethyle cellulose water insoluble used as non- aqueous (alcoholic) solution (5%): for moisture sensitive drugs & it may retard tablet disintegration. - methyl cellulose (MC), hydroxypropyl cellulose (HPC)  Sodium alginate 6- Polyvinylpyrrolidine (PVP): concentration 2% (used as aqueous or alcoholic solution). C. Disintegrants A disintegrant is a substance that facilitates the breakdown of the tablet into smaller fragments upon contact with GI fluids more rapid dissolution. Steps of disintegration 1- Water wet then penetrates the pores of the tablets - The outer surface of the tablets must be easily wetted by water to allow disintegration. - If the tablets is very compact (completely non porous) it will not allow the penetration of water. 2- The tablets disintegrate in granules which de-aggregate into particles. Tablet disintegration Granules deaggregation Particles Slow rate of Rapid rate of Moderate rate dissolution dissolution of dissolution Drug in solution in GI fluid Absorption Drug in blood 12 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi Mechanism of action 1- Increase the hydrophilicity of the outer surface of the tablet. 2- Increase the porosity of the tablet by being water soluble, so, dissolve leaving pores. 3- By swelling in contact with water, so, creat an internal pressure inside the tablet to promote the disintegration. Theories of disintegration The mechanism by which the tablets are broken into small pieces and then produces a homogenous suspension is based on: 1- By porosity and capillary action (wicking) 2- By swelling 3- Because of heat of wetting (air expansion) 4- Due to disintegrating particle/particle repulsive forces 5- Due to deformation 6- Due to release of gases 7- By enzymatic action Adding: 1- After granulation (extragranular) added to produce: a- Rapid disintegration b- Disintegration of the tablet into granules with small surface area 2- Before granulation (intragranular) added to produce: a- Slow disintegration b- Disintegration of the tablet into very fine particles with high surface area 3- Both (intragranular and extragranular) added in two steps: a- Apportion is added to drug diluent mixture (intragranular) b- The other portion is mixed with dry granules before compression (extragranular) 13 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi Other factors than the presence of disintegrants can affect significantly the disintegration time of compressed tablets: 1- The binder 2- Hardness 3- Lubricants 4- Evolution of carbon dioxide as in effervescent tablets 5- porosity Examples: 1- Starch (in concentration 5%, but if more rapid disintegration is desired increase to 10-15%). It swells to 0.25 fold its original volume in acidic medium. 2- Cellulose (ex: methyl cellulose & carboxymethyl cellulose) 3- Clays (ex: veegum and bentonite) may also be used, but they are limited to colored tablets only since they produce off-white appearance. In addition, they are less effective than other disintegrants especially the new ones. Super disintegrants They are used when rapid disintegration is required such as in orodispersible tablets. Used in low conc. (2 to 4%) but they are completely effective Examples (highly increase the porosity of the tablet): - Cross-linked cellulose croscarmelose (swells to 4-8 folds its original volume in acidic media in less than 10 sec.) - Cross-linked polymer crospovidone - Cross-linked starch sodium starch glycolate (Explotab®) (swells to 7-12 folds its original volume in acidic media in less than 30 sec.) 14 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi D. Lubricants The lubricants are materials used to reduce the friction during tablet ejection between the tablet and walls of the die and punches. Advantages of lubricants 1- Facilitate tablets ejection and prevent their sticking in the die. 2- Prolong the life of the die. 3- Decrease the liberated heat (friction heat). Mechanism of action of the lubricants 1- Fluid lubrication (Hydrodynamic): this mechanism is used for explain the action of liquid lubricants. In general, all liquids (especially oily ones) decrease the friction between two surfaces. 2- Boundary lubrication: this mechanism is used for solid lubricants. In this type, the polar portion of the lubricant attached to the metal and prevent tablet sticking with the die. - + - + Lubricant molecules Die wall - + - + Notes:  The lubricants should be added in the last step (just before compression).  The particle size of the lubricants is very important; they should be 200 mesh in size or finer. As a general rule, as the particle size of the lubricants increase, their efficacy decrease. 15 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi  The amount of the lubricant in the formula should not exceed 1% since these materials are water insoluble thus retard water penetration and decrease dissolution rate.  The mixing time of the lubricant with the formula should be 2-5 min. Over mixing decrease the lubricant efficacy because it causes the penetration of the lubricant from the surface to the core of the formula.  The mixing rate is also important; high mixing rate causes the penetration of the lubricant inside the core of the formula and thus, decreases the lubricant efficacy. Examples: Mineral oils such as liquid paraffin have been applied on the granules as fine spray. The problem with using this type of lubricants is the production of spots on the produced tablets. Magnesium and calcium stearate are the most widely used lubricants due to their efficacy. These lubricants should not be used with acidic drugs like aspirin. Stearic acid is less effective than magnesium and calcium stearate. It should not be used with alkaline drugs. Zinc stearate is inert with good lubricating property and small particle size. It is used effectively in direct compression. Talk may also be used as lubricant. Poly ethylene glycols (PEG) with molecular weight of 400-600 are used as lubricants in cases when water solubility is important. PEG are water soluble, but less effective than stearate group. They may be used as powder or solution to be sprayed on the formula. Problem due to lubricants 1- They may reduce tablet strength due to their interference with the bonding between the particles during compression. (thus may counteract the role of binder) 16 Lec. 2 Industrial pharmacy Dr. Ali Saeed Aljaberi 2- They may retard tablet disintegration and dissolution such as Mg stearate because most lubricants are hydrophobic (counteract the role of disintegrant). To overcome these waterproofing characteristics, sodium lauryl sulphate is sometimes included. 3- Alkaline metal stearate (aluminum stearate) and talk are incompatable with some drugs e.g. aspirin and ascorbic acid. It is preferable to use hydrogenated vegetable oil or stearic acid with aspirin. How to avoid this negative effect 1- Minimum amount of lubricants to be used. 2- More hydrophilic substances are suggested as alternative e.g. surfactants and polyethylene glycol. 3- Combination of hydrophilic and hydrophobic may be also useful. 4- Lubricants are added to granules before compression in finely divided form. E. Glidants Glidants are used to promote the flow of granules or powders by reducing the friction between the particles themselves. - They are used in the formulation for direct compression. - They are added to the granules before tableting to ensure proper flowability of tablet mass for high production speed. Examples: - Traditional glidant is Talk powder - The most common glidant today is colloidal silicon dioxide (airosil®) 0.2% by weight. - Silica particle are very fine so they adhere to the surface of other ingredients and improve the flow by reducing interparticular friction. - Mg stearate is mainly used as lubricant but also can be used as glidant ( ± 15% but not more than ± 25%. a- If all the 10 tablets deviate from the average drug content by less than ± 15% the batch is accepted. b- If more than one tablet deviate from the average drug content by more than ± 15% the batch is rejected. c- If only one tablet deviate from the average drug content by more than ± 25% the batch is rejected. d- If only one tablet deviate from the average drug content by more than ± 15% but less than ± 25% the batch is accepted but: 1- If the other 20 tablets deviate from the average drug content by less than ± 15% the batch is accepted. 2- If only one tablet from the other 20 tablets deviate from the average drug content by more than ± 15% the batch is rejected. 3 Lec. 3 Industrial pharmacy Dr. Ali Saeed Aljaberi 4- Testing mechanical properties of the tablet (hardness & friability Importance: 1- To ensure that the tablets will withstand handling, shipping, and transport. 2- To ensure that the tablets are produced with the required hardness and friability. 3- To ensure that the hardness of the tablet will not affect the disintegration and dissolution. A- Testing hardness of tablets 1- Monsanto or stokes hardness tester It is manual, so, the results are less accurate (not consistent pressure) 2- Erweka hardness tester: Most widely used, measure hardness electrically, and more accurate as it use computer. Test: 1- Collect 6 tablets by random manner all are brushed. 2- Measure the force required to break each tablet in kg/cm 2 (4 kg is considered to be minimum for a satisfactory tablet) force applied diametrically to tablet and it must be broken into 2 equal halves to be considered breaking (where capping or lamination or splitting is not counting) Results: If the tablets broken by force: 1- Less than 4 kg/cm2 the batch is rejected. 2- 4-9 kg/cm2 the batch is accepted. 3- More than 9 kg/cm2 the batch is accepted but make other quality control tests: a- If the hardness is high but good disintegration & dissolution the batch is accepted. b- If the hardness is high but delayed disintegration & dissolution the batch is rejected. 4- Not more than 2 tablets can fail in the test. 5- If one or two tablets failed the test is repeated on another 12 tablets not more than 2 tablets in the 18 tablets can fail in the test. 4 Lec. 3 Industrial pharmacy Dr. Ali Saeed Aljaberi B- Testing the friability of the tablets The friability is measured by Roche friabilator - Drum with curved stand on which the tablets are placed & the height of this stand is 12 inches (inch=2,54 cm). - The drum is attached to a motor that rotate the drum with constant speed = 25 rpm the test is done for 4 min. (i.e. the drum rotate 100 times) the tablets fall in the drum 100 times from height 6 inches. 1- Collect 20 tablets by random manner all are brushed weighted find the initial weight (W1). 2- Place the tablets in the drum and fix the cover. 3- The drum rotate for 4 min. at 25 rpm i.e. the drum rotate 100 times. - Monitor the tablets: if one tablet or more broken (capping, or lamination, or splitting) during the test the batch is rejected. 4- If no breakage, remove the tablets re-brush re-weight them to find the final weight (W2). 5- Calculate % friability = (W1-W2/W1) X 100 6- A loss up to 1% in weight is accepted (in some pharmacopoeias 0.8%). Results: 1- If only one tablet or more broken during the test the batch is rejected. 2- If no tablets broken during the test & the loss in weight is not more than 1% (or 0,8%) the batch is accepted. 3- If no tablets broken during the test & the loss in weight is more than 1% (or 0.8%) the batch is rejected. An apparatus with 2 drums can be used and the 2 drums are used separately. If the tablets are slightly stick to the drum during rotation simple knocking on the drum from outside can solve the problem. 5 Lec. 3 Industrial pharmacy Dr. Ali Saeed Aljaberi 6- Testing physical properties of the tablet (disintegration and dissolution) a- Disintegration test: measure the time required for the tablet to disintegrate (in vitro) qualitative test The apparatus simulate the in vivo conditions: 1- A water bath is temperature adjusted at 37±2oc (35 – 39) by a thermostat. 2- In which a beaker is placed (its capacity is 1 L). 3- Inside the beaker, there is a basket holding 6 tubes these tubes are open from top and bottom, where the bottom is covered with 10 mesh screen (i.e. 10 openings per the linear inch). 4- The basket moves up and down at a constant rate (28-32 cycle/min). 5- The beaker is filled with 800 ml disintegration fluid which is a simulated GI fluids: a- Purified water for preliminary testing. b- Or 0.1 N HCl pH 1.2 simulate gastric fluid. c- Or phosphate buffer pH 7.2 to 7.4 simulate intestinal fluid. # Collect 18 tablets by random and representative manner # Six tablets are placed in the tubes measure the time required for complete disintegration of each tablet which occurs when: 1- The tablet is fragmented to large particles, which is fragmented to smaller particles that can all pass the mesh screen. 2- The tablet disintegrate by erosion and become smaller till it can pass the mesh screen this occur if the diluent is highly water soluble (ex: lactose) or if the tablet contains a water soluble polymer. 3- The tablet disintegrate by erosion into insoluble soft mass residue remain in the tube having wet core this occur if the tablet contains waxy polymer. The test is stopped and the remaining part is pressed - If it has wet core the disintegration is done. - If it still have dry core, the test is re-continued. # The test is passed when: all tablets disintegrate within the specified time: 1- If 1 or 2 tablets fail to disintegrate within the specified time the test is repeated with another 12 tablets 16 of the 18 tablet should disintegrate within the specified time. 6 Lec. 3 Industrial pharmacy Dr. Ali Saeed Aljaberi 2- The specified time: - Uncoated tablets within 15 min. - Effervescent tablets within 5 min. - Soluble tablets within 3 min. - Sugar coated tablets within 60 min. - Film coated tablets within 30 min. Results: 1- If all tablets disintegrate within the specified time the batch accepted. 2- If more than 2 tablets fail to disintegrate within the specified time the batch is rejected. 3- If 1 or 2 tablets fail to disintegrate within the specified time the batch accepted but the test is repeated with another 12 tablets: a- If not more than 2 tablets in the 18 tablets fail to disintegrate within the given time the batch accepted. b- If more than 2 tablets in the 18 tablets fail to disintegrate within the given time the batch is rejected. Disintegration testing for entering coated tablets Collect 6 tablets by random and representative manner 1- The 6 tablets must not disintegrate (i.e. no sign of disintegration) in 0.1N HCl pH 1.2 within 2 h (N.B. the gastric transit time is from 0.5 – 2 h). 2- But disintegrate within 1 h in phosphate buffer pH 7.2 to 7.4 (simulate intestinal fluid). b- Dissolution testing Measure the time required for a given % of drug in the tablet to dissolve (in vitro) quantitative test. Placing the tablets in a flask containing the dissolution fluid [simulate GI fluids (0.1N HCl pH 1.2 or phosphate buffer pH 7.2 to 7.4)] in a water bath its temperature is adjusted at 37 ±0.5oC by a thermostat. The volume of the dissolution fluid (variable): determining the volume of the dissolution fluid to achieve the sink condition. - The drug will dissolve till equilibrium between the amount of the drug in the tablet and the amount of the drug in the solution after the equilibrium, no more drug will dissolve (because the driving force for 7 Lec. 3 Industrial pharmacy Dr. Ali Saeed Aljaberi dissolution which is the concentration gradient will equal zero at equilibrium). - To overcome this, we must achieve the sink condition by controlling the volume of the dissolution fluid: # To achieve the sink condition, the volume of the dissolution fluid must be 3-10 times the solubility of the drug in the tablet. # For example: if the tablet contain 1 mg drug and the solubility of drug is 1 mg in each 100 ml 3-10 times the 100 ml is used as dissolution flyuid i.e. the volume of the dissolution fluid must be 300-1000 ml no equilibrium will occur and the drug will continue to dissolve. Methods for dissolution testing: 1- Stirred vessel methods a- Rotating basket method (USP method 1) - Tablet is placed in small rotating basket formed of mesh screen at a distance of 2.5 cm from the bottom of the flask. - The basket rotate at 80 rpm to maintain the drug concentration homogenous throughout the dissolution fluid. - Sample from the dissolution fluid taken (from the middle) after different time interval if rapid disintegration tablet, take after short time interval & if sustained release, take after long time intervals. - The bottom of the flask is rounded. - The basket descend in the fluid slowly to avoid formation of large amounts of air bubbles which can affect the dissolution of the drug (resist the dissolution of the drug) errors. - The basket is a screen from all sides except the upper part. b- The paddle method (USP method 2) - The bottom of the flask is rounded. - There is 2.54 cm (1 inch) between the paddle and the bottom of the container. - The speed of rotation (if not specified) = 80 rpm. The test carried on 12 tablets 6 tablets are tested 1- Calculate amount of drug dissolved (in mg) after each time interval. 2- Find % of drug dissolved after each time interval = amount dissolved at time/labeled amount X 100 8 Lec. 3 Industrial pharmacy Dr. Ali Saeed Aljaberi 3- Plot the percent of drug dissolved (on y axis) against time (on x axis). The withdrawal of the samples should be through a filter to avoid withdrawal of undissolved particles. Sometimes, the volume of the dissolution fluid will be larger than the capacity of the flask so that, another method called the continuous flow cell method is used to achieve the sink condition. 2- Continuous flow cell method - The tablet is placed in flow cell through which fresh dissolution fluid is pumped at a controlled rate at different time intervals then automatically sucked for analysis. - The sink condition will be achieved as the concentration gradient will be always maximum (no equilibrium will occur). - Used if (advantages): a- The volume of the dissolution fluid required to achieve the sink condition is larger than the capacity of the flask in the stirred methods. b- In case of floating tablets in the stirred methods, the tablet will not surrounded by the dissolution fluid from all directions. c- The dissolution of the drug in the tablet is very slow. 9 Lec. 3 Industrial pharmacy Dr. Ali Saeed Aljaberi Tablet manufacturing Tablet press machines used for tablet compression A- Single punch press (eccentric press): one die & one pair of punch. 1- The feed present in a hopper is connected to a hopper shoe that moves on the die by rotational movement. 2- When the shoe is located over the die the feed flow from the hopper to the shoe, then to the die by gravity filling of the die by the feed. 3- Then the shoe moves beside the movable upper punch descends to compress the feed over the stationary lower punch. 4- After compression, the lower punch moves upward to eject the tablet. - The amount of feed filling the die controlled by the position of the lower punch. - Pressure of compression and so strength of the tablet controlled by the upper punch. - The output of this press is 200 tablet/min. so, used only for trial, small scale production-formulation development. - The speed of the machine affects the quality of the produced tablets. - The speed is controlled to produce the maximum efficacy of the tablet press. 10 Lec. 3 Industrial pharmacy Dr. Ali Saeed Aljaberi Compaction cycle = stages of tablet formation= steps of tablet compression 1- Die filling Granules are preferred in die filling due to higher flowability & easier compression. 2- Tablet formation (compression) 3- Tablet ejection The tablet is knocked away by the shoe that refill the die Technical problems: 1- Dose variation: Due to: - The filling of the die is not uniform a- Over filling which can cause over weight of tablets high tablet weight variation. b- Or under filling which cause under weight of the tablets low tablet weight variation. - Variation in the flowability: which depend on: a- Particle size and shape. b- Amount of lubricant and glidant. Overcome by: the flowability must be improved. 2- Low mechanical strength (friability): due to: - Insufficient of binder or weak binder - Low pressure of compression. Overcome by: - Sufficient binder - Proper binder - Increase pressure of compression 3- Capping or lamination or splitting of tablet: due to: - Excess fine particle that may entrap air. - Too much pressure of compression. - Imperfect punches surfaces (bad polishing). - Worn dies. - Uneven and poorly machined punches - Unsuitable formula. - Low melting point substances or eutectic mixture 11 Lec. 3 Industrial pharmacy Dr. Ali Saeed Aljaberi Overcome by: - Entrapped air cause capping. - Reduce the pressure of compression. - Punch should have smooth surfaces - Worn die should be replaced. - Movement of punches should be adjusted. - Amount of binder and lubricant should be accurate. 4- Chipping: due to - Sticking on punch faces - Too dry granules - Too much binding Overcome by - Dry the granules properly or increase lubrication - Moisten the granules - Optimize binding or use dry binder 5- Cracking: due to - Large size of granules - Too dry granules - Tablet expansion - Granulation too cold Overcome by - Reduce granule size, add fine - Moisten the granules properly and add proper amount of binder - Improve granulation, add dry binder - Compress at room temperature 6- Adhesion of tablet to surface of punches (picking): due to: - Insufficient drying - Insufficient amount of lubricant & glidant - Punches have rough surfaces (bad polishing) - Low melting point substances or eutectic mixtures 12 Lec. 3 Industrial pharmacy Dr. Ali Saeed Aljaberi Overcome by: - Sufficient lubricant & glidant - Punches should have smooth surfaces 7- High friction with the die surface during tablet ejection (sticking): due to: - Insufficient amount of lubricant & glidant. - Worn die Overcome by: - Sufficient amount of lubricant & glidant. - Worn die should be replaced 8- Mottling: due to - Difference in color between drug and excipients - Dye migration Overcome by - Use of colorants - Change the solvent, binder, reduce drying temperature, or grind the granules to small size - Incorporate fine powder adhesives such as acacia and tragacanth into the product before adding the granulating fluid, or to disperse a dry color additive during the powder blending step. Important properties of powder that must be controlled to ensure good tablet formation: 1- Particle size and shape which affect segregation and flowability. 2- Compactability 3- Adhesion & friction properties. These properties can be controlled by: 1- Using excipients 2- How the ingredients of the tablet are combined. 13 Lec. 3 Industrial pharmacy Dr. Ali Saeed Aljaberi Unit operations used during this are: 1- Particle size reduction (by grinding) & enlargement (by granulation). 2- Drying B- Rottary press (multistation press): - The punches and dies (from 30 to 60 dies) are fixed to a turret that spins round - The punches are driven together by two fixed cams (upper & lower cam). - The top of the upper punch (the punch head) sits on the upper cam edge, while the bottom of the lower punch sits on the lower cam edge. - They need very sophisticated lubrication systems (because of high speeds). Stages occurring during compression: 1- Top punch is withdrawn from the die by the upper cam. Bottom punch is low in the die so powder falls in through the hole and fills the die. 2- Bottom punch move up and adjust the powder weight – it raises and expel some powder. Excess powder is removed. 3- Top punch is driven into the die by upper cam. Bottom punch is raised by lower cam. Both punch heads pass between heavy rollers to compress the powder. 4- Top punch is withdrawn by the upper cam. Lower punch is pushed up and expels the tablet. Tablet is removed from the die surface by surface plate. 5- Return to stage one. 14 Lec. 3 Industrial pharmacy Dr. Ali Saeed Aljaberi Adv.: 1- The output is up to 10000 tablet/min. 2- Available in different speed. 3- Adaptation to perform multiple functions like: multiple feed, forced feed, and compression – coating process. 4- Ease of maintenance. C- Computerized, hydraulic press (simulator): - Each step is highly controlled. - Applications (researches & studies rather than production): a- Investigation of drug sensitivity to production conditions. b- Research the ideal conditions for production c- To predict scale up problems 15