PHR 303 Pharmaceutical Technology - II Friday, April 28, 2017 PHR 303 Pharmaceutical Technology - II

TO BE INCLUDED IN FINAL SYLLABUS 1. Formulation & Manufacturing of Tablets 2. Common Tableting Problems & Evaluation of Tablets 3. Tablet Coating 1. Sustained Release Drug Delivery Systems 2. Aerosol Science & technology 3. Design & operation of clean rooms 4. Parental products 5. Ophthalmic products 6. Packaging technology 7. Blood products & plasma substitutes

TOPICs: Formulation, Manufacturing, Evaluation & Coating of Tablets Friday, April 28, 2017

Tablets may be defined as solid pharmaceutical dosage forms containing drug substances prepared either by compression or molding methods. Although it is possible to manufacture in a wide range of shape, official tablets are defined as circular sizes with either flat or convex faces.

Friday, April 28, 2017

Advantages of Tablets 1. Large scale manufacturing is feasible in comparison to other dosage forms. Therefore, economy can be achieved. 2. Accuracy of dose is maintained since tablet is a solid unit dosage form. 3. Tailor made release profile can be achieved. 4. Longer expiry period and minimum microbial spillage owing to lower moisture content. 5. As tablet is not a sterile dosage form, stringent environmental conditions are not required in the tablet department. Fri, Feb 20 2015

…continued 6. Ease of packaging (blister or strip) and easy handling. 7. Ease of product identification because of huge number of shapes and color. 8. Easy to transport in bulk. Emergency supply supplies can be carried by patients. 9. Organoleptic properties (taste, appearance and odour) are best improved by coating of tablet. Fri, Feb 20 2015

…continued 10. Product identification is easy and markings done with the help of grooved punches and printing with edible ink. 11. Different types of tablets are available like buccal, floating, colon targeting, effervescent, dispersible, soluble, and chewable, etc. 12. In composition to parenterals dosage form, a doctor or a nurse is not required for administration. I.e. self administration is possible. 13. In comparison to capsules, tablets are more tamperproof. Fri, Feb 20 2015

Disadvantages of tablets 1. Drugs not absorbed or extensively degraded into GI tract cannot be made into tablets 2. It is difficult to convert a high dose poorly compressible API into a tablet of suitable size for human use. 3. Difficult to formulate a drug with poor wettability, slow dissolution into a tablet. 4. Slow onset of action as compared to parenterals, liquid orals and capsules. Fri, Feb 20 2015

…continued 5. The amount of liquid drug (e.g. Vitamin E, Simethicone) that can be trapped into a tablet is very less. 6. Difficult to swallow for kids, terminally ill and geriatric patients. 7. Patients undergoing radiotherapy cannot swallow tablet. Fri, Feb 20 2015

Essential qualities of a good tablet They should be accurate and uniform in weight The drugs should be uniformly distributed throughout the tablets The size and shape should be reasonable for easy administration The tablets should not be too hard that it may not be disintegrate in the stomach After administration it should disintegrate readily They should be attractive in appearance They should not have any manufacturing defects like cracking, capping or discoloration

Absorption of drug from tablets

Friday, April 28, 2017

Compressed tablets- Immediate release tablets Coated tablets Sugar coated tablets Film coated tablets-Enteric coated tablets Compression Coating & Layered Tablets Modified release/Sustained release/Controlled release Fri, Feb 20 2015

Examples Chewable- Antacid tablet Soluble tablets- Aspirin tablet Effervescent tablets- vitamin C Mouth dissolving tablets (orally disintegrating tablets)- Loratidin tablets Fri, Feb 20 2015

Friday, April 28, 2017

Classes & Designations of Tablets Oral Tablets for Ingestion Compressed Tablets Multiple Compressed Tablets Enteric Coated Tablets Repeat Action Tablets Delayed Action Tablets 6. Sugar coated Tablets Film Coated Tablets Effervescent Tablets Chewable Tablets Chocolate Coated Tablets Tablets Used in the Oral Cavity Buccal Tablets Sublingual Tablets Lozenges or Troches Dental Cones Tablets Administered by Other Routes 1. Implantation Tablets Tablets Used to Prepare Solutions Hypodermic Tablets Dispensing Tablets 3. Compressed Tablet Triturates Tablets Manufactured by Molding 1. Tablet Triturates 2. Hypodermic Tablets Friday, April 28, 2017

Tablet excipients Compressed tablets usually consist of active medicaments mixed with a number of inert substances known as excipient or additives i.e. all non – drug components of a formula are termed excipients or additives. Although these additives are termed as inert but they have a great influence on stability, bioavailability and the process by which the dosage forms are prepared. Friday, April 28, 2017

Classification of tablet excipients According to the functions, tablet excipients are classified as follows: 1. Diluent (or filler) 2. Disintegrant 3. Solution binder 4. Dry binder 5. Glidant 6. Lubricant 7. Antiadherent 8. Sorbent 9. Flavor 10. Colorant Friday, April 28, 2017

Examples of substances used as excipients in tablet formulation Type of Excipient Example of substances FIller Lactose, Sucrose, Glucose, Mannitol, Sorbitol, Calcium phosphate, Calcium carbonate, Cellulose Disintegrant Starch, Cellulose, Crosslinked polyvinyl pyrrolidine, Sodium starch glycolate, Sodium CMC Solution Binder Gelatin, Polyvinyl pyrrolidine, Cellulose derivatives (hydroxypropylmethyl cellulose, Sucrose, Starch Dry Binder Cellulose, Methylcellulose, Polyvinyl pyrrolidine, Polyethylene glycol Glidant Silica, Magnesium stearate, Talc Lubricant Magnesium stearate, Stearic acid, Polyethylene glycol, Liquid Paraffin Antiadherent Magnesium stearate, Talc, Starch, Cellulose Examples of substances used as excipients in tablet formulation Friday, April 28, 2017

Regardless of why an excipient is selected, they must meet certain criteria in the formulation. These include the following: 1. they must be nontoxic & acceptable to the regulatory agencies in all countries where the product is to be marketed. 2. They must be commercially available in an acceptable grade in all countries where the product is to be manufactured. 3. Their cost must be acceptably low. 4. They must not be contradicted by themselves (eg sucrose) or because of a component (eg sodium) in any segment of the population. 5. They must be physiologically inert. Pg 325 LAchman Friday, April 28, 2017

6. They must be physically and chemically stable by themselves and in combination with the drug(s) and other tablet components. 7. They must be free of any unacceptable microbiological ‘load’. 8. They must be color-compatible (not produce any off-color appearance). 9. If the drug product is also classified as a food, (certain vitamin products), the diluent and other excipients must be approved direct food additives. 10. They must have no deleterious effect on the bioavailability of the drug (s) in the product. Friday, April 28, 2017

Granulation Granulation is the process in which powder particles are made to adhere to form larger particles called granules. Pharmaceutical granules typically have a size range between 0.2 and 4.0 mm, depending on their subsequent use. Reasons for granulations: To prevent segregation of the constituents in the powder mix To improve the flow properties of the mix To improve the compression characteristics of the mix Friday, April 28, 2017

Other reasons… The granulation of toxic materials will reduce the hazard of the generation of toxic dust which may arise when handling powders. Materials which are slightly hygroscopic may adhere and form a cake if stored as a powder. Granulation may reduce this hazard as the granules will be able to absorb some moisture and yet retain their flow ability because of their size. Granules being denser than the parent powder mix occupy less volume per unit weight. Friday, April 28, 2017

Methods of granulation Two types: 1. Dry granulation and 2. wet granulation Dry granulation: In the dry granulation methods the primary powder particles are aggregated at high pressure. It is done by two processes i.e. i. slugging and ii. roller compaction. Wet granulation: It involves the massing of a mix of dry primary powder particles using a granulating fluid. The granulating fluid contains a solvent that must be volatile so that it can be removed by drying, and non-toxic. Friday, April 28, 2017

Granulation mechanisms A. Particle bonding mechanisms B. Granule formation mechanisms Friday, April 28, 2017

A. Particle bonding mechanisms To form granules bonds must be formed between powder particles so that they adhere and these bonds must be sufficiently strong to prevent breakdown of the granules to powder in subsequent handling operations. The five primary bonding mechanisms between particles are: Adhesion and cohesion forces in the immobile liquid films between individual primary powder particles. Interfacial forces in mobile liquid films within the granules The formation of solid bridges after solvent evaporation Attractive forces between solid particles Mechanical interlocking Friday, April 28, 2017

B. Mechanisms of granule formation Nucleation Transition Ball growth Friday, April 28, 2017

Pharmaceutical granulation equipment Wet granulator: There are three main types of granulator used in the pharmaceutical industry for wet granulation Shear granulator High-speed mixer/granulator Fluidized-bed granulator Friday, April 28, 2017

Pharmaceutical granulation equipment Fluidized-bed granulator The fluid bed granulator performs the following steps: The powder particles are fluidized in a stream of air Granulating fluid is sprayed from a nozzle onto the powder bed The wet granulates are then dried in the heated fluidizing air system Friday, April 28, 2017

Pharmaceutical granulation equipment Fluidized-bed granulator Friday, April 28, 2017

Pharmaceutical granulation equipment Dry granulator: Slugging: The dry powders can be compacted using a large heavy duty rotary tablet machine. This process is known as slugging. The compacts made in the process is known as slugs. A hammer mill is then used to break down the compacts or slugs. Friday, April 28, 2017

Pharmaceutical granulation equipment Dry granulator: Roller compaction: In this process powder mix are squeezed between two counter rotating rollers to form a compressed sheet. This formed sheet is normally weak and brittle and breaks immediately into flakes. These flakes are later broken into granules. Friday, April 28, 2017

Pharmaceutical granulation equipment Roller compactor Friday, April 28, 2017

Roller compaction: (a) Alexanderwerk and (b) Hutt types. Friday, April 28, 2017

Tablet Granulations: Basic Characteristics There are many formulation and process variables involved in the granulation step, and all of these can affect the characteristics of the granulations produced. Therefore, methods to measure certain granulation characteristics have been developed to monitor granulation suitability for tableting. Friday, April 28, 2017

Particle Size & Shape Surface Area Density Strength & Friability Flow Properties Repose Angle Hopper Flow Rates Compaction Friday, April 28, 2017

Difference between compression and compaction Powder compression is defined as the reduction in volume of a powder owing to the application of a force. Because of the increased proximity of particle surfaces accomplished during the compression, bonds are formed between particles which provide coherence to the powder, i.e. a compact is formed. Compaction is defined as the formation of a solid specimen of defined geometry by powder compression. Friday, April 28, 2017

Tablet Manufacturing Stages in tablet formation Tablets are prepared by forcing particles into close proximity to each other by powder compression, which enables the particles to cohere into a porous, solid specimen of defined geometry. The compression takes place in a die by the action of two punches, the lower and the upper, by which the compressive force is applied Friday, April 28, 2017

The process of tableting can be divided into three stages (sometimes known as the compaction cycle). Friday, April 28, 2017

1. Die filling This is normally accomplished by gravitational flow of the powder from a hopper via the die table into the die (although presses based on centrifugal die filling are also used). The die is closed at its lower punch. Friday, April 28, 2017

2. Tablet formation The upper punch descends and enters the die and the powder is compressed until a tablet is formed. During the compression phase, the lower punch can be stationary or can move upwards in the die. After maximum applied force is reached, the upper punch leaves the powder, i.e. the decompression phase. Friday, April 28, 2017

3. Tablet ejection During this phase the lower punch rises until its tip reaches the level of the top of the die. The tablet is subsequently removed from the die and die table by a punching device. Friday, April 28, 2017

Tablet compression machines Tablets are made by compressing a formulation containing a drug or drugs with excipients on stamping machines called presses. Tablet compression machines or tablet presses are designed with the following basic component: Hopper for holding and feeding granulation to be compressed Dies that define the size and shape of the tablet Punches for compressing the granulation within the dies Cam tracks for guiding the movement of the punches Feeding mechanisms for moving granulation from the hopper into the dies Friday, April 28, 2017

Tablet compression machines Various types of machines are used. Tablet presses are classified as either single-punch or multi-station rotary presses. They are as follows: Single punch machine Multi punch machine Rotary tablet machine High speed rotary tablet machine Multi layer rotary tablet machine Multi-station presses are termed rotary because the head of the tablet machine that holds the upper punches, dies, and lower punches in place rotates. As the head rotates, the punches are guided up and down by fixed cam tracks, which control the sequence of filling, compression, and ejection. Friday, April 28, 2017

Single punch tablet press Friday, April 28, 2017

A tablet machine’s output is regulated by 3 basic characteristics of its design: Number of tooling sets Number of compression stations Rotational speed of the press There are many modifications and options that can be obtained from various manufacturers. One modification, found on most modern high-speed tablet presses, is the use of hydraulic or pneumatic pressure to control the pressure rolls in place of the older spring type pressure…..gives a smoother pressure or compressive load force over a longer period of time. Friday, April 28, 2017

Methods of Tablet Manufacture There are 3 basic methods of preparation of compressed tablets. Each method has its own advantages, disadvantages and limitations. Friday, April 28, 2017

The manufacture of granulations for tablets compression may follow one or a combination of three established methods: Wet granulation Dry granulation or compression granulation & Direct compression

Steps for Tablet Production

Friday, April 28, 2017

In-Process Quality Control During the compression of tablets, in-process tests are routinely run to monitor the process, including tests for tablet weight, weight variation, hardness, thickness, disintegration, and various evaluations of elegance. The in-process tests are performed by production and/or quality control (QC) personnel. Friday, April 28, 2017

The following standards or quality control tests are carried out on compressed tablets: General appearance Size and shape Unique identification of marking Organoleptic properties Hardness 6. Friability 7. Weight variation test 8. Content uniformity test 9. Disintegration test 10. Dissolution test

Coated Tablets Friday, April 28, 2017

Tablet Coating Tablet coating is a process by which an essentially dry, outer layer of coating material is applied to the surface of a dosage form in order to confer specific benefits that broadly range from facilitating product identification to modifying drug release from the dosage forms. 28 April 2017

Tablet Coating Principle Tablet coating is an additional step in the manufacturing process… increases the cost of the product. Therefore, the decision to coat a tablet is usually based on one or more of the following objectives: 28 April 2017

Reasons for Coating To mask the taste, odor, or color of the drug To provide physical and chemical protection for the drug To control the release of the drug from the tablet To protect the drug from the gastric environment of the stomach with an acid-resistant enteric coating To incorporate another drug or formula adjuvant in the coating to avoid chemical incompatibilities or to provide sequential drug release To improve the pharmaceutical elegance by use of special colors and contrasting printing. NOTE: see Aulton for more reasons 28 April 2017

There are 3 primary components involved in tablet coating: Tablet properties Coating process: coating equipment, parameters of the coating process, facility & ancillary equipment, automation in coating process Coating components 28 April 2017

Tablets to be coated must possess following properties: 1. Tablets must be resistant to abrasion and chipping. 2. Tablets should have smooth surface for proper coating. 3. The tablets must be in constant motion during the early drying phase to prevent tablet agglomeration. 4. The spherical shape of tablet is preferable for coating process. This will allow the tablets to roll freely in the coating pan with minimal tablet-to-tablet contact. 28 April 2017

Equipments for Tablet Coating Standard (conventional) coating pan Perforated coating pan Fluidized bed (air suspension) coater Pellegrini Pan System Accela-Cota System Air Suspension System Immersion Sword System Hi-Coater Systems Immersion Tube System Driacoater System Glatt Coater System 28 April 2017

Spray Application Systems Low pressure, air atomized Coating Process Spray Application Systems High pressure, airless Low pressure, air atomized 28 April 2017

Types of Coatings Sugar Coating Film Coating Compression Coating 28 April 2017

Materials Used in Film-Coating The coating materials may be a physical deposition of the material on the tablet substrate, or they may form a continuous film with a wide variety of properties depending upon the composition of the coating formulations. Examples of physical deposition of the coating materials are the techniques of sugar, shellac, and wax coatings. A wide variety of polymers are used commercially for tablet coating. Mon, Sept 01, 2014

An ideal film coating material should have the following attributes: Solubility in solvent of choice for coating preparation. Solubility required for the intended use eg, pH-dependent solubility (enteric coating) Capacity to produce an elegant looking product Stability in the presence of heat, light, moisture, air, and the substrate being coated. The film properties should not change with aging. Essentially no color, taste, or odor. Compatibility with common coating solution additives. Mon, Sept 01, 2014

7. Nontoxicity with no pharmacological activity, and ease of application to the particles or tablets. 8. Resistance to cracking, and provision of adequate moisture, light, odor, or drug sublimation barrier when desired. 9. No bridging or filling of the debossed tablet surfaces by the film former. 10. Ease of printing procedure on high-speed equipment. Mon, Sept 01, 2014

No commercially available material fulfils all requirements of an ideal coating material. A pharmaceutical scientist usually formulates a coating solution to achieve certain desired properties for the film-coated product. The available film formers can be classified into nonenteric and enteric materials. Mon, Sept 01, 2014

Film-coating formulations Currently, the majority of film-coating processes involves the application of a coating liquid where a significant proportion of a major component (the solvent/vehicle) is removed by means of a drying process that is concurrent with the application of that coating liquid. Film-coating formulations typically compromise: 1. Polymer 2. Plasticizer 3. Colourants 4. Solvent/vehicle Wed, Aug 27, 2014

Friday, April 28, 2017

1. It should either dissolve or disperse the polymer system. Some important considerations for an ideal solvent system are as follows: 1. It should either dissolve or disperse the polymer system. 2. It should easily disperse other coating solution components into the solvent system. 3. Small concentrations of polymers (2 to 10%) should not result in an extremely viscous solution system (>300cps), creating processing problems. 4. It should be colourless, tasteless, odorless, inexpensive, nontoxic, inert, and nonflammable. 5. It should have a rapid drying rate (the ability to coat a 300 kg load in 3 to 5 hours). 6. It should have no environmental impact. Wed, Aug 27, 2014

Differences between sugar & film coating Fri, Feb 20 2015