Technology of Making Tablets Murat Kizaibek Tablets are

Technology of Making Tablets Murat Kizaibek

• Tablets are solid dosage forms consisting of active ingredient(s) and suitable pharmaceutical excipients. They may vary in size, shape, weight, hardness, thickness, disintegration and dissolution characteristics, and in other aspects. They may be classyfied, according to the method of manufacture, as compressed tablets or molded tablets.

Advantages • Production aspect – Large scale production at lowest cost – Easiest and cheapest to package and ship – High stability • User aspect (doctor, pharmacist, patient) – Easy to handling – Lightest and most compact – Greatest dose precision & least content variability

Disadvantages • Some drugs resist compression into dense compacts • Drugs with poor wetting, slow dissolution, intermediate to large dosages may be difficult or impossible to formulate and manufacture as a tablet that provide adequate or full drug bioavailability • Bitter taste drugs, drugs with an objectionable odor, or sensitive to oxygen or moisture may require encapsulation or entrapment prior to compression or the tablets may require coating

Types of tablets • • 1)compressed tablets 2)sugar coated tablets 3)film coated tablets 4)enteric coated tablets 5)effervescent tablets 6)chewable tablets 7)dispersible tablets 8)sustained release tablets

• • 9)multilayer tablets 10)sublingual tablets 11)toroches 12)buccal tablets 13)implant tablets 14)hypodermic tablets 15)solution tabletc 16)vaginal tablets

EXCIPIENTS FOR COMPRESSED TABLETS Compressed tablets usually contain a number of pharmaceutical adjuncts, known as excipients, in addition to the medicinal substance. The use of appropriate excipients is important in the development of the optimum tablets. Excipients determine the bulk of the final product in dosage forms such as tablet, capsule, etc. , the speed of disintegration, rate of dissolution, release of drug, protection against moisture, stability during storage, and compatibility. Excipients should have no bioactivity, no reaction with the drug substance, no effect on the functions of other excipients, and no support of microbiological growth in the product.

A. DILUENTS Diluents increase the volume to a formulation to prepare tablets of the desired size. Widely used fillers are lactose, dextrin, microcrystalline cellulose starch, pregelatinized starch, powdered sucrose, and calcium phosphate.

• The diluent is selected based on various factors, such as the experience of the manufacturer in the preparation of other tablets, its cost, and compatibility with other formulation ingredients. For example, in the preparation of tablets or capsules of tetracycline antibiotics, a calcium salt should not be used as a diluent since calcium interferes with absorption of the antibiotics from the GI tract.

B. BINDERS • Binders promote the adhesion of particles of the formulation. Such adhesion enables preparation of granules and maintains the integrity of the final tablet. As listed in the Table, Commonly used binding agents include: starch, gelatin and sugars (sucrose, glucose, dextrose, and lactose).

Examples of Binders Carboxymethylcellulose, sodium Karaya gum Cellulose, microcrystalline(Avicel®) Starch, pregelatinized Ethylcellulose Tragacanth gum Hydroxypropyl methylcellulose Poly(acrylic acid) Methylcellulose Polypvinylpyrrolidone Acacia gum Gelatin Agar Dextrin Algin acid Glucose Guar gum Molasses

C. LUBRICANTS • Lubricant is a substance capable of reducing or preventing friction, heat, and wear when introduced as a film between solid surfaces. It works by coating on the surface of particles, and thus preventing adhesion of the tablet material to the dies and punches. Glycerylmonostearate(USP/NFCH 2(OH)CH 2 O 2 CC 17 H 35) is one example of a lubricant. Lubricants play more than one role in the preparation of tablets as described below.

• 1. Lubricants improve the flow of granules in the hopper to the die cavity. • 2. Lubricants prevent sticking of tablet formulation to the punches and dies during formulation. • 3. Lubricants reduce the friction between the tablet and the die wall during the tablet’s ejection from the tablet machine. • 4. Lubricants give a sheen to the finished tablets.

• Commonly used lubricants include: talc, magnesium stearat, calcium stearate , stearic acid, hydrogenated vegetable oils and (PEG).

D. DISINTEGRATORS • The breakup of the tablets to smaller particles is important for dissolution of the drug and subsequent bioavailability. Disintegrators promote such breakup. To rupture or breakup of tablets, disintegrating agents must swell or expand on exposure to aqueous solution. Thus, the most effective disintegrating agents in most tablet systems are those with the highest wa-ter uptake property. In general, the more hydrophilic, the better disintegrating agents are therefore highly hydrophilic. A list of typical disinte-grants is tabulated in Table

E. WETTING AGENTS • Water molecules attract each other equally in all directions. Water molecules on the surface, however, can only be pulled into the bulk water by water molecules underneath, since there are no water molecules to pull in the opposite direction. The surface tension of water is strong enough to support the weight of tiny insects such as water striders. The surface ten-sion in action can be visualized by placing a small drop of alcohol on a thin layer of water. Alcohol with lower surface tension mixes with water causing reduction in the surface tension in the local region. Owing to the higher surface tension of water in the neighbor, water is pulled from the alcohol dropped region into the neighbor, and this leads to the formation of a dry spot in the middle of the water layer.

Compressed tablet manufacture • The classification of manufacturing methods granulation wet granulation: suitable for drugs that are stable to moisture and heat dry granulation: suitable for drugs that are sensitive to moisture and heat direct compression powder compression : suitable for drugs that are sensitive to moisture and heat, fill material possessing, good flowability and compressibility crystal compression：suitable for drugs with proper crystal form and good flowability

wet granulation adhesive drug smash sieving mix prilling excipients lubricant dry processing granule mix press

dry granulation adhesive drug smash excipient mix press sieving mix press cake processing smash granule

powder compression adhesive drugs smash excipients sieving mix press

• crystal compression drugs smash adhesive sieving mix excipients mix press

• wet granulation technology • (一)wet granulation methods and equipment: • 1. Extrusion grain methods and equipment: first prescription drug powder and the auxiliary materials mixed evenly to join adhesive soft material system, then with soft material compulsory extrusion way through has a certain size screen hole and granulating method.

wet granulation

Compressed tablet manufacture —— wet granulation • The steps of wet granulation weighing and blending the ingredients(disintegrant) preparing a damp mass (liquid binder) Internal(内加法) screening the damp mass into pellets or granules drying the granulation sizing the granulation by dry screening adding lubricant and disintegrant, and blending tableting by compression External(外加法)

The classification of tablet presses • Tablet presses: a. single-punch presses b. multi-station rotary presses

The main components of single-punch tablet presses Core components: die lower punch upper punch

The basic mechanical process of tableting with single-punch presses a) filling material b) scraping away the excessive granulation c) forming a tablet by compression d) pushing up the tablet to stage surface e) shoving the tablet aside

A picture of multi-station rotary press hopper feed-frame head: upper turret, lower turret, die table upper turret die table lower turret

The core components and compression cycle of rotary presses A: upper punch B: die cavity C: die D: lower punch The compression is applied by both the upper punch and the lower punch. The compression cycle of a rotary tablet press

Compressed tablet manufacture —— Direct compression tableting Suitable for 1) granular chemicals possessing free flowing and cohesive properties e. g. potassium chloride 2) chemicals added with special pharmaceutical excipients which impart the necessary qualities for the production of tablets by direct compression

The direct compression tableting excipients include: a) fillers, as spray-dried lactose, microcrystals of alphamonohydrate lactose, sucroseinvert , sugar – corn starch mixtures, microcrystalline cellulose, crystalline malt and dicalcium phosphate; d) disintegrants, as direct-compression starch, sodium carboxymethyl starch, cross-linked carboxymethylcellulose fiber, and cross-linked polyvinylpyrrolidone; c) lubricants, as magnesium stearate and talc; d) glidants, fumed silicon dioxide

• Sophora Alopecuruldes L．Seed Tablet optimization

excipient powder of sophora AIopecuroides L． Seed press 1％Magnesium stearate mix 制软材 prilling 、 processing granule mix

table 1 the influence of different adhesive to Tablet hardness formula 1 adhesive 10% Starch Hardness （Kg） 0. 68 2 10%PVP（ water） 0. 83 3 10%CMC-Na 0. 75 4 10%PVP (Ethanol) particles deformed

table 2 formula the influence of different fillers to Tablet hardness 5 6 7 fillers starch Pregelati lactose nized starch Hardnes s（Kg） 0. 68 0. 77 3. 14 8 10%PVP ( Ethanol) 3. 55

table 3 factor level Factor level A [The amount of Microcrstalline cellulose(g)] 80 120 160 A [Concentration of PVP solution（%，g/ml)] 10 15 20

table 4 Result of Orthogonal test A×B Test NO. 1 2 3 4 5 6 7 8 9 K 1 K 2 K 3 R× 6 　　A 1 1 1 2 2 2 3 3 3 17. 8 24. 2 24. 4 6. 6 　　B 1 2 3 23. 0 21. 8 21. 6 1. 4 Result 1 2 3 2 3 1 2 21. 4 22. 5 1 2 3 3 1 2 2 3 1 22. 2 22. 0 22. 2 1. 1 0. 2 0. 6 Ⅰ Ⅱ 3. 1 2. 8 3. 2 4. 1 4. 0 4. 2 4. 0 3. 9 2. 9 3. 1 2. 7 4. 4 4. 1 3. 4 3. 8 4. 2 Total 6. 0 5. 9 8. 5 8. 1 8. 5 7. 8 8. 1

table 5 variance source SS total variance 5. 658 A Analysis of variance table V MS F P 4. 698 2 2. 349 33. 562 0. 0001 B 0. 191 2 0. 096 1. 366 0. 3034 A×B 0. 139 4 0. 035 0. 993 0. 4077 error 0. 630 9 0. 070

table６　微晶纤维素用量影响苦豆子片硬度的ｑ检验（ｎ＝６） Comparison 两均数之 group 差 standard value of q Number error of group ｑ界值 α =0. 05 α= 0. 01 P A 1 and. A 3 -1. 1 0. 1074 -10. 241 3 4. 34 6. 33 <0. 01 A 1 and. A 2 -1. 0 0. 1074 -9. 310 2 3. 46 5. 24 <0. 01 A 2 and. A 3 -0. 1074 -9. 310 2 3. 46 5. 24 >0. 05

Tablet coating The reasons for tablet coating 1) to protect the medicinal agent against destructive exposure to air and/or humidity; 2) to mask the taste of the drug; 3) to provide special characteristics of drug release; 4) to provide aesthetics or distinction to the product; 5) to prevent inadvertent contact by nonpatients with the drug substance

The general methods involved in coating tablets are as follows 1) sugarcoating tablets 2) film-coating tablets 3) enteric coating 4) pan coating 5) fluid-bed or air suspension coating 6) compression coating

The sugarcoating of tablets may be divided into the following steps: 1) waterproofing and sealing (if needed) 2) subcoating 3) smoothing and final rounding 4) finishing and coloring (if desired) 5) polishing

film-coating machine

1) waterproofing and sealing (if needed) aim: to prevent the components from being adversely affected by moisture; one or more coats; shellac , zein , or a polymer as cellulose acetate phthalate 2) Subcoating aim: to bond the sugar coating to the tablet and provide rounding a) 3 to 5 subcoats of a sugar-based syrup are applied. The sucrose and water syrup also contains gelatin, acacia, or PVP.

b) When the tablets are partially dry they are sprinkled with a dusting powder, usually a mixture of powdered sugar and starch but sometimes talc, acacia, or precipitated chalk as well. c) Then drying the tablets. Repetition (15 to 18 times) the subcoating process until the tablets are of the desired shape and size.

3) smoothing and final rounding aim: to complete the rounding and smooth the coatings 5 to 10 additional coatings of a thick syrup; This syrup is sucrose-based with or without additional components as starch and calcium carbonate. 4) finishing and coloring aim: to attain final smoothness and the appropriate color several coats of a thin syrup containing the desired colorant

5) imprinting aim: to impart identification codes and other distinctive symbols to the product The imprint may be debossed, embossed, engraved, or printed on the surface with ink. 6) polishing aim: to render the tablets the desired sheen/gloss/luster a) pans lined with canvas cloth impregnated with carnauba waxand/or beeswax b) Pieces of wax may be placed in a polishing pan c) light-spraying of the tablets with wax dissolved in a nonaqueous solvent

Tablet coating —— film-coating tablets 1) The disadvantages of sugarcoating process a) time-consuming b) requiring the expertise of highly skilled technicians c) doubling the size and weight of the original uncoated tablets d) may vary in size from batch to batch and within a batch e) large tablets are not as easily swallowed as are small tablets.

2) The advantages of film-coating process a) coated tablets having essentially the same weight, shape, and size as the originally compressed tablet b) The coating is thin enough to reveal any identifying monograms. c) far more resistant to destruction by abrasion than are sugar-coated tablets d) the coating may be colored to make the tablets attractive and distinctive.

3) The components of nonaqueous film-coating solutions: a) film former: e. g. CAP b) alloying substance: to provide water solubility or permeability to the film e. g. PEG c) plasticizer: to render flexibility and elasticity to the coating e. g. castor oil d) surfactant: to enhance spreadability of the film e. g. polyoxyethylene sorbitan derivatives e) opaquants and colorants: e. g. titanium dioxide, FD&C or D&C dyes f) sweeteners, flavors, and aromas: saccharin, vanillin g) glossant: beeswax h) volatile solvent: alcohol-acetone mixture

4) The components of a typical aqueous film-coating solutions: a) film-forming polymer (7 -18%): e. g. cellulose ether polymers as HPMC, HPC and MC b) plasticizer (0. 5 -2. 0%): e. g. glycerin, propylene glycol, PEG, diethyl phthalate, and dibutyl subacetate c) colorant and opacifier (2. 5 -8%): FD&C or D&C lakes and iron oxide pigments d) water

5) Some problems with aqueous film-coating a) picking and peeling the appearance of small amounts or large amounts of film fragments flaking from the tablet surface b) orange peel effect roughness of the tablet surface due to failure of spray droplets to coalesce c) mottling an uneven distribution of color on the tablet surface d) bridging filling-in of the score-line or indented logo on the tablet by the film e) tablet erosion disfiguration of the core tablet

5) Some problems with aqueous film-coating a) picking and peeling the appearance of small amounts or large amounts of film fragments flaking from the tablet surface b) orange peel effect roughness of the tablet surface due to failure of spray droplets to coalesce c) mottling an uneven distribution of color on the tablet surface d) bridging filling-in of the score-line or indented logo on the tablet by the film e) tablet erosion disfiguration of the core tablet

The reasons for capping, splitting or laminating of tablets 1) air entrapment 2) not immaculately cleaned or not perfectly smoothed punches 3) too great a proportion of fine powder 4) Tablets have aged or have been stored improperly

quality standards and compendial requirements The apparent physical features of compressed tablets: 1) shape: round, oblong, unique 2) thickness: thick or thin 3) diameter: large or small 4) flat or convex 5) unscored or scored in halves, thirds and quadrants 6) engraved or imprinted with an identifying symbol and/or code number 7) coated or uncoated 8)colored or uncolored 9) number of layer. The die and punches determine the physical features of compressed tablets.

quality standards and compendial requirements Ø Other physical specifications and quality standards: tablet weight variation content uniformity tablet thickness tablet hardness tablet disintegration drug dissolution Ø in-process controls Ø verification after the production

quality standards and compendial requirements —— tablet weight and Chp weight variation Ø Chp weight variation: sample amount 20 tablets Ø Tablets should comply with the following Average weight Weight variation limit Less than 0. 3 g ± 7. 5% 0. 3 g or more ± 5% requirements stated in the table below.

quality standards and compendial requirements —— tablet weight and Chp weight variation The procedure of weight variation determination in Chp: Weigh accurately 20 tablets and calculate the average weight, then weigh individually each of the 20 tablets. Compare the weight of each tablet with the labelled tablet (if no labelled weight is stated, compare the weight of each tablet with the average weight calculated). No more than 2 of the individual weights exceed the weight variation limit stated in the table above and none doubles the limit.

quality standards and compendial requirements —— tablet hardness and friability Tablet hardness 1)The greater the pressure applied, the harder the tablets. 2) The hardness required by different tablets a) lozenges and buccal tablets: hard (dissolve slowly) b) the tablets for immediate drug release: soft 3) measurement a) special dedicated hardness testers b) multifunctional equipment

quality standards and compendial requirements —— content uniformity Ø applys to potent drug of low dose. Ø USP method, 10 tablets are individually assayed for their content. The amount of active ingredient in each tablet lies within the range of 85% to 115% of the label claim and the RSD is less than 6. 0%.

quality standards and compendial requirements —— tablet hardness and friability (continued) Friability 1) It is used to determine a tablet’s durability 2) Method: allowing the tablets to roll and fall within the rotating apparatus (friabilator); determine the loss in weight; 3) requirement: weight loss ≤ 1%

quality standards and compendial requirements —— tablet dissolution 1) The importance of in vitro dissolution test a) to guide the formulation and product development process toward product optimization b) to monitor the performance of manufacturing process c) to assure bioequivalence from batch to batch d) as a requirement for regulatory approval for product marketing for products registered with the FDA and regulatory agencies of other countries.

2) The goal of in vitro dissolution is to provide a reasonable prediction of the product’s in vivo bioavailability. Basis: The combinations of a drug’s solubility and its intestinal permeability are supposed as a basis for predicting the likelihood of achieving a successful in vivo – in vitro correlation (IVIVC).

Considered are drugs determined to have: a) high solubility and high permeability (IVIVC may be expected. ) b) low solubility and high permeability (IVIVC may be expected. ) c) high solubility and low permeability d) low solubility and low permeability

3) The formulation and manufacturing factors affecting the dissolution of a tablet a) the particle size of the drug substance b) the solubility and hygroscopicity of the formulation c) the type and concentration of the disintegrant, binder, and lubricant used d) the manufacturing method, particularly, the compactness of the granulation and the compression force e) the in-process variables

4) Test method a) A volume of the dissolution medium is placed in the vessel and allowed to come to 37℃± 0. 5℃. b) The stirrer is rotate at the specified speed. c) At stated intervals, samples of the medium are withdrawn for chemical analysis 5) Requirement for rate of dissolution The specific required rates of dissolution are different for tablets containing different medicinal agents. e. g. not less than 85% of the labeled amount is dissolved in 30 minutes

6) Inconsistencies in dissolution occur not between dosage units from the same production batch, but rather between batches or between products from different manufacturers. Pooled dissolution testing has emerged. This process recognizes the concept of batch characteristics and allows pooled specimens to be tested.