Ceutics III Clinical Powder Granules Lecture 1 PDF

1 Dr. Soha Kandil PhD Assistant Professor of Pharmaceutics and Drug Manufacturing department Email: kandil.2009 @hot mail.com Building Room: 237 third floor Office hr. Sunday 11.30 – 1.30 Tuesday 9- 11  Construction of pharmaceutical dosage form (medicine)...

1 Dr. Soha Kandil PhD Assistant Professor of Pharmaceutics and Drug Manufacturing department Email: kandil.2009 @hot mail.com Building Room: 237 third floor Office hr. Sunday 11.30 – 1.30 Tuesday 9- 11  Construction of pharmaceutical dosage form (medicine) 1- API 4-Container 3-Additive 5-Package 2-Excipient insert 6-Label  Solid: Powders, Granules, Capsules, Tablets, Implants, Suppositories. Semisolid: Ointment, Creams, Gels, Paste, Poultice, plaster. Liquid: Colloids, Solutions, Suspension, Emulsion, Powder for making solution or suspension. Gases: Aerosols, pure gases (O2, CO2, He,…..)  Pharmaceutical powder is a mixture of finely divided drugs and/or chemicals in a dry form that may be intended for internal use (oral powders) or external use (topical or dusting powder). Powders are subdivided solids which are classified in the BP (British pharmacopeia) according to the size of their constituent particles of range from 1.25 µm to 1.7 mm in diameter. Another classification of powders is based on the 4 manner of their dispensing.  Granules are prepared aggregates of powdered materials to form a larger particle (2-4 mm). Granules may be used as such (granules of medicinal value) or in making tablets and capsules (because of better flowability of granules compared to powders). 5 Advantages of Powders: 1) To solve problems of insolubility, instability and microbial contamination of some drugs. ex: crude vegetable drugs, and antibiotics. 2) When a bulky drug that has a large dose is to be administered, ex: in case of indigestion, constipation and diarrhea. They used to contain large amounts of light materials such as Magnesium Carbonate. (take a teaspoonful of the powder and swallow with water). 3) Difficulty in swallowing tablets and capsules. (Small children and old people) 4) Faster absorption from the GIT 5) When the patient must to mix the ingredients 6 before administration. Disadvantages of powders : 1) Time consuming to prepare and pack. 2) bulky to carry. 3) Powders may spill when they are being opened. 4) Patient may misunderstand the correct method of use. 5) It is undesirable to take bitter or unpleasant tasting drugs by oral ad-ministration. 6) It is difficult to protect powders containing hygroscopic, deliquescent or aromatic materials from decomposition. 7) Uniform, individually wrapped doses of powders (sachets) are required and this may increase the manufacturing expense. 8) Powder must be a homogeneous blend of all of the components and must be of the most advantageous particle size. 9) It is not an accurate way of administering medicines, So potent substances should never be given in the form of 7 bulk powders. Advantages of granules over powder : 1) Granules flow better than powders 2) Granules also eliminate or control dust. 3) Granules increase compressibility. 4) Granules have smaller surface area than a comparable volume of powders. This makes granules more stable physically and chemically, no cake formation 5) Granules are more easily wetted by a solvent than are certain powders, so that granules are also preferred in making solutions. Example: Principen® (ampicillin) 8 6)The granules also contain colorants, flavorants, and other pharmaceutical ingredients, so the resulting solution or suspension has all the desired medicinal and pharmaceutical features of a liquid pharmaceutical 7)Granules produce particle-size uniformity, thus content uniformity. 8)Segregation of the constituents of the powder mixture could be avoided by granulation. (small particles and denser particles concentrated in the base of the container and vice versa), 9 Classification of powders according to the manner of their dispensing Powders may be provided to the patient in bulk or divided. 1) Bulk powders for external use: (a) Dusting powders (b) Douche powders (c) Dental powder (d) Insufflations (e) Snuffs 2) Bulk powders for internal use. 3) Simple and compound powders for internal use. 4) Powders for reconstitution a) Oral antibiotic b) Powder for injection 5) Effervescent granules 6) Cachets 10 1)Bulk powders for external use: 11  (a) Dusting powders Uses: Dusting powders usually contain substances such as zinc oxide, starch and boric acid or natural mineral substances such as kaolin or talc. These are used externally for local application not intended for systemic action. They are employed chiefly as lubricants, protectives, absorbents, antiseptics,, astringents and antiperspirants. Characteristics and requirements Homogeneity. Non-irritability, also it should not be applied to broken skin. Free flowability. Good spreadability and covering capability. 1 2 Adsorption and absorption capacity. Very fine state of subdivision. If desired, powders should be micronized. less than 10 microns in diameter Capacity to protect the skin against irritation caused by friction, moisture or chemical irritants. In some cases, powder should be sterilized such Talc, it may be contaminated with pathogenic microorganisms such as - Clostridium tetani, and hence it should be sterilized by dry heat. Absorption is the process in which a fluid is dissolved by a liquid or a solid (absorbent). Adsorption is the process in which atoms, ions or molecules from a substance (it could be gas, liquid or dissolved solid) adhere to a surface of the adsorbent 13  (a) Dusting powders Packaging and dispensing: Dusting powders should preferably be dispensed in sifter-top containers. Such containers provide the protection from air, moisture and contamination as well as convenience of application. Currently some foot powders and talcum powders have been marketed as pressure aerosols. 14  (b) Douche powder Uses: These powders are intended to be used as antiseptics or cleansing agents for a body cavity; most commonly for vaginal use although they may be formulated for nasal, otic or ophthalmic use also. They usually are used after being dissolved in water. 1 5 Characteristics and requirements Douche powder formulation often include aromatic oils To eliminate agglomeration and to ensure complete mixing, it becomes necessary to pass them through a sieve # 40 or 60. Packaging and dispensing: They can be dispensed either in sachets or wide mouth glass bottles, but the former are preferred because of protection afforded against air and moisture. 16  (c) Dental powders Uses: Dental powders are rarely prescribed. This preparation is a type of dentifrice meant for cleaning the teeth. Characteristics and requirements Dental powders contain detergents, abrasives, antiseptics, coloring and flavoring agents incorporated in a suitable base. Generally, the base is calcium carbonate. 1 7 The detergent is in the form of soap and the abrasive action is provided by finely powdered pumice stone. Essential oils are added to provide flavor and freshness to the mouth as well as antiseptic action. Essential oils are easily absorbed by calcium carbonate and pumice.  This makes the uniform distribution of the oil difficult. Best results are obtained if the oil is triturated in the solids taking considerable care to distribute it uniformly. 18  (c) Dental powders Packaging and dispensing: they are dispensed in wide- mouth jars or bottles. 19  (d) Insufflations Uses: Insufflations are a class of powders meant for application to the body cavities e.g., ear, nose, vagina etc. Characteristics and requirements The powder must be extremely fine and must find an entry to the cavity deep enough to bring about its action at the site. It is delivered to the affected part in a stream with the help of a device called an insufflator, which blows the powder to the site. 20 Some of the insufflations contain volatile liquid ingredients which may require uniform distribution in the powder. If these liquid ingredients are present in large quantity, the liquid portion may have to be evaporated. If it is present in small portions should not be removed by evaporation but only incorporated by trituration in the powder. 21  (d) Insufflations Packaging and dispensing: insufflations are packaged in pressurized form i.e., aerosols. Aerosols contain the medication in a stout thick container with a suitable valve, The delivery of the powder being accomplished by a liquefied or compressed gas propellant of very low boiling point. On pressing the actuator of the valve, the propellant delivers the medication in a stream. 22  (e) Snuffs These are finely divided solid dosage forms of medicaments dispensed in flat metal boxes with hinged lid. These powders are inhaled into nostrils for decongestion, antiseptic, and bronchodilator action. 23 2. Bulk powders for internal use Bulk powders contain many doses in a wide-mouth container that is suitable to remove the powder by a teaspoon. The non-potent substances are used in bulk powder form such as antacid, laxative, purgative, etc. 24 3. Simple and compound powders for internal use Simple powders are similar formulations to bulk powders but individual doses are separately wrapped. These are unit dose powders normally packed in properly folded papers and dispensed in envelopes, metal foil, small heat-sealed plastic bags or other containers.  However, modern packaging materials of oil and plastic laminates have replaced paper wrapping (WHY?) because they offer superior protective qualities and are amenable to use on high-speed packaging machines. 25 4. Powders for reconstitution They are bulk powders intended to be reconstituted just before use. They are usually used to protect drugs against hydrolysis by water or enhance stability of the active constituents. Examples of these powders are: a) Oral antibiotic For stability problems the antibiotic is prepared in a dry form (powder or granules) and packed in a sealed bottle, a given amount of water is added before use. Once it is reconstituted the patient should be warned of the short shelf life (usually 1-2 weeks). 26  b) Powders for injection They may be classified as bulk or divided powders. Injections of drugs that are unstable in solution must be made immediately prior to use and are presented as sterile powders in ampoules. Sterile water for injection is added from a second ampoule and the injection is used immediately. 27 5. Effervescent granules: Advantages of effervescent granules 1) Attractive dosage form for the public. 2) The carbonated solution masks undesirable taste of the drug. 3) The liberated CO2 gas is used as a therapeutic agent; it increases gastric secretions and hence facilitates digestion, and it acts as anti-nauseant. 4) Using granules rather than powders decreases the rate of solution and prevents uncontrollable effervescence. 28 Disadvantages of effervescent granules 1) Instability in presence of moisture. So, it is important to protect effervescent granules from moisture during manufacture and storage to prevent premature reaction between acids and base. 2) Problems in packaging and storage. 29 Packaging and dispensing effervescent granules : There are three alternative methods of dispensing depending upon the nature of prescription. 1-As bulk powder: If the effervescent salts are prescribed to be the dispensed in bulk form, no granulation is necessary. The ingredients are mixed uniformly, and directions stated on the label to add the prescribed quantity to water, before use. 30 2-As divided powder doses: If the effervescent salt is prescribed in divided doses, the ingredients which cause effervescence on mixing with water are enclosed separately in papers of different color. The patient is advised to take one powder of each color and add to water, before use. 3-As bulk or divided granular powder: In the third case the product contains all the ingredients mixed together in a granular form. 31 6. Cachets Cachet as a unit dosage form was extremely popular sometime back. Presently cachets are seldom used and have been replaced by capsules. Cachets, like capsules, can be easily filled and sealed at the dispensing counter. This dosage form holds larger quantity of the medication as compared to capsules. Since the cachets are made of flour and water they are easily damaged in handling. Further this dosage form offers little protection against light and moisture. 32  Quality control of Powders Particle sizesvery fine, fine, moderately coarse, coarse, and very coarse. Particle size can affect several factors which are: Dissolution rate: The smaller the particle size, the faster is the dissolution Suspendability: In suspension preparation, it is important to have a good suspendability (i.e., ability to maintain uniform dispersion in liquid vehicle) of particles. Uniform distribution: In a powder mixture or capsule and tablets preparation, the ability of a drug to have uniform distribution is essential. 3 3 Penetrability: For intra-respiratory applications, the penetrability of inhaled particles to reach a desired location within the respiratory tract is important (1–5 μm) Non-grittiness: In dermal ointments, creams, and ophthalmic preparations, nongritty fine powders should be used. Fine particles of 50–100 μm in size can be used for this purpose. 34  Particle-size analysis 1-Sieving A powder mass is placed on top of a sifter (mechanical shaker) that is made of a series of screens with sequentially smaller apertures. The sieve motion allows subsieving. sieve size and sieve numbers are inversely proportional. Higher sieve number has a smaller size opening or vice versa. In the United States, Tyler standard and US standard (ASTM E11-70) are commonly used. The two standards are different slightly but can be used interchangeably. Sieve 38 45 53 63 75 90 106 125 150 180 212 250 300 355 425 500 600 710 850 2,360 opening (mm) No. 400 325 270 230 200 170 140 120 100 80 70 60 50 45 40 35 30 25 20 8 35 esh/inch)  Particle-size analysis 2 -Microscopy Particle size is measured using a calibrated grid background. the size and size distribution can be analyzed by an image analyzer. The resolution limit by light microscopy is 0.2 μm. Electron microscopy is useful for the particles < 0.2 μm. 3-Sedimentation Rate The terminal settling velocity of particles through a liquid medium in a gravitational and centrifugal environment can be used to calculate the particle size based on Stokes’ law 36 Stokes' Law to apply, you must consider a spherical grain of radius r and density d1 falling through a fluid of density d2 and viscosity µ. The velocity of fall V is then given by Stokes Law V=2/9(gr2)(d1-d2)/µ V = velocity of fall (cm/sec) g = acceeleration of gravity (cm/sec2) r = "equivalent" radius of particle d1 = density of particle (g/cm3) d2 = density of medium (g/cm3) µ = viscosity of medium (g/cm-sec) 37 4-Coulter Counter Coulter counter determines the volume distribution of particles suspended in an electrolyte-containing solution. When a particle passes through a small orifice, it blocks the electric current. The information on particle volume is used for calculating particle size assuming a spherical shape. coulter counter which is used to detect number of particles present in an electrolyte and to determine the size of those particles... 38 Particle-size analysis 5- Light Scattering Other automatic particle-size measuring instrument employs the light scattering principle. This can be performed either in solution or in the dry powder state. 6- Gas Adsorption The surface area of powdered materials can be measured by adsorption of solute from solution or of a gas. This method results in the specific surface area (area/unit mass). Usually, an inert gas, such as nitrogen, is adsorbed as a monolayer and the total volume of gas adsorbed is used to calculate the specific surface area, which in turn provides information on the particle size. 39 Flow Properties of Powders and powder flowability The descriptions “good flow behavior” or “poorly flowing powder” are usually used to describe the flow properties of the powder. Good flowing powder usually means that bulk powder flows easily, i.e., it does not consolidate much and flows out of a silo or a hopper due to the force of gravity alone and no flow promoting devices are required. Products are poorly flowing if they have flow 40 The flow properties of powders depend on several parameters: Particle size distribution Particle shape Chemical composition of the particles Moisture Temperature 41  42 Chapter 2 Granulation Dr. Soha Kandil PhD Assistant Professor of Pharmaceutics and Drug Manufacturing department Email: kandil.2009 @hot mail.com Building Room: 237 third floor Office hr. Sunday 11.30 – 1.30 Tuesday 9- 11  Granulation Definition: Is the process in which primary powder particles are made to adhere to form larger particles called granules.  Characters Have a size range between 0.2 and 4.0 mm, In the majority of cases this will be in the production of tablets or capsules.  Granulation normally commences after initial dry mixing of the necessary powdered ingredients so that a uniform distribution of each ingredient through the mix is achieved. After granulation the granules will either be packed (when used as a dosage form), or they may be mixed with other excipients prior to tablet compaction or capsule filling.  In a suitable formulation A number of different excipients will be needed in addition to the drug. The common types used are diluents, to produce a unit dose weight of suitable size, and disintegrating agents, which are added to aid the break-up of the granule when it reaches a liquid medium, e.g. on ingestion by the patient. Adhesives in the form of a dry powder may also be added, particularly if dry granulation is employed. These ingredients will be mixed before granulation. Methods of granulation Granulation methods can be divided into two types: wet methods, which use a liquid in the process, and dry methods in which no liquid is used. 1. Dry granulation In the dry methods of granulation the primary powder particles are aggregated under high pressure. There are two main processes. A large tablet (known as a 'slug') is produced in a heavy-duty tabletting press (a process known as 'slugging') or the powder is squeezed between two rollers to produce a sheet of material ('roller compaction'). In both cases these intermediate products are broken using a suitable milling technique to produce granular material, which is usually sieved to separate the desired size fraction. The unused fine material may be reworked to avoid waste. This dry method may be used for: Drugs that do not compress well after wet granulation, or Those which are sensitive to moisture. roller compaction 2. Wet granulation Wet granulation involves the massing of a mix of dry primary powder particles using a granulating fluid. The fluid contains a solvent, which must be: Non-toxic Volatile so that it can be removed by drying. The granulation liquid may be used alone or, more usually, as a solvent containing a dissolved adhesive (also referred to as a binder or binding agent) which is used to ensure particle adhesion once the granule is dry. In the traditional wet granulation method the wet mass is forced through a sieve to produce wet granules which are then dried. Reasons for granulation The reasons why granulation is often necessary are as follows: 1. To prevent segregation of the constituents of the powder mix. Segregation (or demixing) is primarily due to: Differences in the size density of the components of the mix, the smaller and/or denser particles concentrating at the base of a container while the larger and/or less dense ones above them. An ideal granulation will contain all the constituents of the mix in the correct proportion in each granule, and segregation of the ingredients will not occur. It is also important to control the particle size distribution of the granules because, although the individual components may not segregate, if there is a wide size distribution the granules themselves may segregate. 2. To improve the flow properties of the mix Many powders, because of their small size, irregular shape or surface characteristics are cohesive and do not flow well. Poor flow will often result in a wide weight variation within the final product owing to variable fill of tablet. Granules produced from such a cohesive system will be larger and more iso diametric, both factors contributing to improved flow properties. 3-To improve the compaction characteristics of the mix Some powders are difficult to compact even if a readily compactable adhesive is included in the mix, but granules of the same formulation are often more easily compacted and produce stronger tablets. This is associated with the distribution of the adhesive within the granule and is a function of the method employed to produce the granule. 4. Other reasons The above are the primary reasons for the granulation of pharmaceutical products, but there are other reasons that may necessitate the granulation of powdered material: a. The granulation of toxic materials will reduce the hazard associated with the generation of toxic dust that may arise when handling powders. b. 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. C. Granules, being denser than the parent powder mix, occupy less volume per unit weight. They are therefore more convenient for storage or shipment.