Pharmaceutics III Solid Dosage Forms PDF

Pharmaceutics III Solid dosage forms Dr. Reem Ragaey Vision: Leadership in the pharmaceutical field on the national level with international recognition of excellence. :‫الرؤية‬. ‫الريادة محليًا والتميز دوليًا في المجال الصيدلي‬ ...

Pharmaceutics III Solid dosage forms Dr. Reem Ragaey Vision: Leadership in the pharmaceutical field on the national level with international recognition of excellence. :‫الرؤية‬. ‫الريادة محليًا والتميز دوليًا في المجال الصيدلي‬  Mission: The Faculty of Pharmacy - Ahram Canadian University, is committed to provide an up- to-date learning environment within a framework of advanced programs that enable the graduate to acquire professional ethics and have the competencies required for the job market. The Faculty, through distinguished calibers, supports effective collaboration with the community and encourages scientific research. :‫الرسالة‬ ‫ جامعة األهرام الكندية بتوفير بيئة تعليمية معاصرة وبرامج متطورة إلعداد خريج يحافظ‬- ‫تلتزم كلية الصيدلة‬ ‫ تدعم الكلية المشاركة المجتمعية الفعالة والبحث‬.‫على أخالقيات المهنة ولديه الجدارات الالزمة لسوق العمل‬.‫العلمي مرتكزة فى ذلك على كوادر بشرية متميزة‬  Lectures: 2hrs/week + 1 lab (1hr/week) Weight of Assessments: Work 5 marks Midterm exam 10 marks Practical exam 25 marks Final written exam 50 marks Oral 10 marks Total 100 marks Learning outcomes: Recognize various properties of different solid dosage forms such as powders, granules, tablets and capsules as well as molded solid dosage forms such as suppositories. Comprehend the principles of reaction order kinetics Assimilate pharmaceutical knowledge to design, prepare and assure quality of different solid dosage forms such as powders, granules, tablets and capsules as well as molded solid dosage forms such as suppositories. Integrate pharmaceutical knowledge in formulating safe and effective pharmaceutical dosage forms. Learning outcomes: Apply reaction order kinetics in validating drug products through shelf life determination. Apply pharmaceutical calculations in compounding, dispensing and storage of solid and molded solid dosage forms. Adopt the principles of stability calculations in predicting the most suitable conditions for storage of different pharmaceutical products.  Powders Definition !? Powder is a solid dosage form composed of mixtures of dry, finely divided drugs and/or chemicals. The size of the particles range from 0.1 micron (0.1 μ) to 1000 micron (1 mm).  The term ‘Powder’ may be used to describe:  The physical form of a material, that is, a dry substance composed of finely divided particles.  Or, it may be used to describe a type of pharmaceutical preparation, that is, a medicated powder intended for: internal (oral administration) external (topical powder) use.  Examples of powder uses: 1. Powdered drugs may be blended with powdered fillers and other pharmaceutical ingredients to fabricate solid dosage forms as tablets and capsules. 2. They may be dissolved or suspended in solvents or liquid vehicles to make various liquid dosage forms. 3. They may be incorporated into semisolid bases in the preparation of medicated ointments and creams.  Micrometrics It is the science and technology of small particles that have definite shape and dimensions. The unit of particle size used is the micrometer (μm),micron(μ),and equal to10-6 m. Before their use in the preparation of pharmaceutical products, solid materials first are characterized to determine the following properties:  Particle size & analysis (size, methods, distribution)  Particle shape, surface area, porosity, densities  Powder flow and compressibility —  I. Particle size Particle size can influence a variety of important factors, including the following: 1. Dissolution rate of particles intended to dissolve; as particle size of the drug decreases the rate of drug dissolution increases. 2. Suspendability of particles intended to remain un-dissolved but uniformly dispersed in a liquid vehicle (e.g., fine dispersions have particles approximately 0.5 to 10 μm). 3. Uniform distribution of a drug substance in a powder mixture or solid dosage form to ensure dose-to-dose content uniformity. 4. Penetrability of particles intended to be inhaled for deposition deep in the respiratory tract (e.g., 1 to 5 μm). 5. Lack of grittiness of solid particles in dermal ointments, creams, and ophthalmic preparations (e.g., fine powders may be 50 to 100 μm in size).  PARTICLE SIZE ANALYSIS  The particles of pharmaceutical powders and granules may range from being extremely coarse, about 10 mm (1 cm) in diameter, to extremely fine, approaching colloidal dimensions of 1 μm or less. In order to characterize the particle size of a given powder, the United States Pharmacopeia (USP) uses these descriptive terms: 1. very coarse 2. Coarse 3. moderately coarse 4. Fine 5. very fine Extremely coarse Extremely fine (1 (10mm in diameter) micron or less)  Methods for particle size determination 1. Sieving: in which particles are passed by mechanical shaking through a series of sieves of known and successively smaller size and the proportion of powder passing through or being withheld on each sieve is determined. 2. Microscopy: Particles are sized through the use of calibrated grid background or other measuring device ( range 0.2 to 100 micrometers)  For submicron particles it is necessary to use either:  TEM(Transmission Electron Microscopy) studies the internal structures of a cell.  SEM(Scanning Electron Microscopy) which can be used to study the details of a sample's surface. 3. SEDIMENTATION RATE: in which particle size is determined by measuring the terminal settling velocity of particles through a liquid medium in gravitational or centrifugal environment (range: 0.8-300 micrometers).  Sedimentation rate may be calculated from Stock’s law. 4. Counter coulter: An apparatus for counting and sizing particles suspended in electrolytes. This suspension is then made to flow through a short insulated capillary section between two electrodes and the voltage of the system is measured. 5. Light scattering or light energy diffraction In which particle size is determined by the reduction in light reaching the sensor as the particle, dispersed in a liquid or gas, passes through the sensing zone (range 0.2500 microns). 6. Laser scattering. Laser holography In which a pulsed laser is fired through an aerosolized particle spray and photographed in three dimensions with a holographic camera, allowing the particles to be individually imaged and sized (range: 1.4~ 100 microns).  II. Powder Flowability Powder Flowability describes the ease with which the powder flows under a specified set of conditions. Factors that affect the flow of powder: 1. Superficial adhesiveness. 2. Shape of the particles: Spherical particles flow quickly while irregular shaped particles flow slowly. 3. Surface of the particles: Wrinkled surface has low flowability while smooth surface has high flowability. 4. The presence of electrostatic charges on the surface of the particles. 5. The hygroscopicity of the powders: Moisture content of particle greatly affects powder’s flowability.  Disadvantages of a bad powder flow: An incomplete & irregular filling of dies or bottles is achieved.  Advantages of good powder flow: Filling the dies in very short time. This means complete and regular filling of dies or bottles.  How to improve powder flowability? 1. Particle’s size & Distribution. 2. Particle Shape & texture. 3. Surface forces. 4. Flow Activators. Alteration of Particle’s size & Distribution Coarse particles are more preferred than fine ones as they are less cohesive. The size distribution can also be altered to improve flowability by removing a proportion of the fine particle fraction or by increasing the proportion of coarser particles ,such as occurs in granulation.  Alteration of Particle Shape & texture Particle’s Shape: Generally , more spherical particles have better flow properties than more irregular particles. Particle's texture: Particles with very rough surfaces will be more cohesive and have a greater tendency to interlock than smooth surfaced particles.  Alteration of Surface Forces Reduction of electrostatic charges can improve powder flowability. (HOW?) Electrostatic charges can be reduced by altering process conditions to reduce frictional contacts (where powder is poured down , the speed & length of transportation should be adjusted). Hygroscopic powders should be stored and processed under low humidity conditions.  Flow enhancer or Glidants  Flow enhancers improve the flowability of the powder by reducing inter-particle friction.  Excipients that have anti-adherent or lubricant properties may enhance powder flowability. Usually glidants are hydrophobic substances 1. Talc 2. Mg stearate 3. Starch 4. Silica gel  Flow properties of powders Tests to evaluate the flowability of a powder. 1.The angle of repose (Ɵ). 2.Hausner ratio. 3.Carr’s compressibility index.  Angle of repose The angle of repose is a relatively simple technique for estimating the flow properties of a powder.  It can easily be determined by allowing a powder to flow through a funnel and fall freely onto a surface.  Angle of repose  The height and diameter of the resulting cone are measured and the angle of repose is calculated from this equation: Tan Ɵ = h/r Or Tan Ɵ = 2h/d  Mass-Volume relationships Types of volume:  True volume (VT)  Bulk volume (VB)  Tapped Volume (V tapped) During tapping, particles gradually pack more efficiently, the powder volume decreases. V0 Vf Before tapping After tapping  The bulk volume of a powder is the volume of an untapped powder sample including the contribution of the inter-particulate void volume. The tapped volume is obtained by mechanically tapping a graduated measuring cylinder or vessel containing the powder sample. Hausner Ratio and Carr’s Index A volume of powder is filled into a graduated glass cylinder and repeatedly tapped for a known duration. The volume of powder after tapping is measured and a calculation performed to calculate the Hausner Ratio or the Carr’s Index (%). Hausner Ratio: if more than 1.25 → poor flowability. Cohesive powders have a high Hausner Ratio and Carr’s Index. Hausner ratio = V bulk / V tapped V bulk = Bulk volume V tapped = tapped volume  Another indirect method of measuring powder flow from bulk density was developed by Carr: Percent compressibility ,according to Carr’s index: % compressibility =(V bulk – V tapped)/ V bulk x100.  Particle size reduction (COMMINUTION OF DRUGS) The process of reducing the particle size of a solid substance. Objectives of Comminution: Facilitate crude drug extraction Increase the dissolution rates of drugs Aid in the formulation process Enhance absorption  Advantages of particle size reduction 1. Better mixing for contents. 2. ↑↑Surface Area →↑wettability→↑dissolution rate. 3. Higher the dissolution, faster the absorption and hence quicker and greater the drug action. 4. Smaller the size of the particle, better the physical stability of the dosage form.  Particle size reduction Techniques used: On small scale (pharmacy): 1. Trituration The pharmacist reduces the size of chemical substances by grinding with a mortar and pestle. A finer grinding action is accomplished by using a mortar with a rough surface (as a porcelain mortar) than one with a smooth surface (as a glass mortar). it has the advantage of being particle size reduction and mixing at the same time. 2. Pulverization: Reducing the size also by using mortar and pestle but by adding solvent that can be easily removed after pulverization (volatile materials such as alcohol for pulverizing camphor). 3. Levigation (wet grinding): Levigation is used in preparation of ointments and suspensions to reduce the particle size and grittiness of the added powders. A paste is formed by combining the powder and a small amount of liquid (the levigating agent) in which the powder is insoluble. Mineral oil and glycerin are commonly used levigating agents.  Particle size reduction On large scale (industrial scale ): Various types of mills and pulverizers may be used to reduce particle size.  Through the grinding action of rapidly moving blades in the comminuting chamber, particles are reduced in size and passed through a screen of desired dimension to the collection container.  Particle size reduction On large scale (industrial scale ): Hammer mill Pulverizer  Mixing (Blending) of Powders Blending is used when two or more substances are to be combined to form a uniform powder mixture. Depending on the nature of the ingredients and the amount of powder, powders may be blended by spatulation, trituration, sifting, and tumbling.  Methods of Mixing of powders On small scale (pharmacy): 1. Spatulation: It is blending small amounts of powders by movement of a spatula through them on a sheet of paper or an ointment tile. It is not suitable for large quantities of powders or for powders containing potent substances, because homogeneous blending is not as certain as other methods. 2. Trituration Trituration may be employed for both comminuting and mixing powders. If simple admixture is desired without the special need for comminution, the glass mortar is usually preferred. When a small amount of a potent substance is to be mixed with a large amount of diluent, the geometric dilution method (sometimes called doubling up technique) is used to ensure the uniform distribution of the potent drug.  In the geometric method, 1.The potent drug is placed on an approximately equal volume of the diluent in a mortar and mixed by trituration. 2.Then , a second portion of diluent equal in volume to the mixture is added , and the trituration repeated. 3.This process is continued by adding equal volumes of diluent to the powder mixture and repeating until all of the diluent is incorporated. 3. Sifting Powders may also be mixed by passing them through sifters (sieves). Sieving usually is employed as a pre- or post-mixing method to separate fine particles from coarse ones. Sifting results in a light, fluffy product. This process is not acceptable for the incorporation of potent drugs into a diluent powder.  (Large-Scale Mixing Equipment) Tumbling The powder enclosed in a large container which rotates generally by a motorized process. Such blenders are widely employed in industry to blend large amounts of powder Double cone V-shape mixer blender Pharmaceutics III Solid dosage forms Lecture 2 Dr. Reem Ragaey  Advantages of powdered dosage forms 1. Solid preparations are more chemically stable than liquid ones (longer shelf life). e.g. the shelf life of powders for antibiotic is 2-3 years but once they are reconstituted with water it is1-2weeks. 2.They are convenient form in which drugs with a large dose are dispensed (Sometimes the doses of some drugs are too bulky to be formed into tablets or capsules of convenient size).  Advantages of powdered dosage forms 3. Children and elderly patients →difficulty in swallowing solid dosage forms →Powders are used either: 1. directly using a spoon or 2. by mixing it with water, milk , or food 3. administered through feeding tube to tube-fed patients. 4-Rapid therapeutic effect: Powders are already taken as small particles  they do not need disintegration, de-aggregation, and dissolution  rapidly dissolved in body fluid and absorbed faster than other solid dosage forms (tablets or capsules).  (1) Disintegration (2) Deaggregation Small drug particles Tablet Granules (3) Dissolution Drug solution (4) Absorption 5- Easier in carrying and handling than liquid dosage forms. 6- Used in blending with medicated application as ointments, suppositories and pastes. Disadvantages of powdered dosage forms 1.Not suitable for: Drugs unstable in atmospheric conditions. Hygroscopic, deliquescent (tending to melt or dissolve in humid environment) and volatile drugs. Bitter, nauseous, corrosive, and unpalatable drugs. Drugs of very small doses (less than 60 mg) cannot be accurately weighed. Drugs which are inactivated in, or cause damage to the stomach. 2. If not individually packed, inaccurate dosing may take place as the patients use different spoons for measuring doses. 3. Bulky to carry as compared to tablets and capsules. 4.The masking of unpleasant taste of drugs may be a problem with this type of preparation.  Medicated powders Powders are mixtures of dry, finely divided drugs and/or chemicals that may be intended for internal or external use. Powders as a dosage form may be provided to the patient in bulk or divided forms.  Classification of powders B- Divided powders A- Bulk powders (internal use). 2- for external use 1- Oral bulk powders e.g., antiseptics e.g., antacids dusting powders laxatives  Bulk Powders The mixed ingredients are packed into a suitable bulk container, such as a wide-mouthed glass jar. The constituents of bulk powders are usually relatively non- potent and non-toxic medicaments with a large dose. Forms of powders commonly dispensed in a bulk form 1-Powders used in a dry form. 2-Powders to be dissolved in water before use. 3-Powders for reconstitution. Examples of Bulk powder for external use: A. Dusting powders. B. Dentifrices. C. Douche powders.  Powders used in a dry form A-Dusting Powders External preparations applied to the skin to achieve surface effect such as lubrication and drying. Dusting powders must be:  homogeneous  Particles are in very fine state of subdivision (very small) to enhance spreading, effectiveness and minimize local irritation.  Should be free-flowing powders that spread uniformly and stick to the skin when applied. The active ingredients must therefore be diluted with materials having reasonably good flow properties, e.g. talc or maize starch.  Dusting powders contain ingredients used for:  Therapeutic  prophylactic  lubricant purposes Dusting Powder may contain:  an anti-bacterial  Anti-fungal infections, e.g. Canesten Powder (clotrimazole)  lubricant e.g. Talc Dusting Powder  Antiseptic  Antiperspirant.  B-Dental cleansing powders (Dentifrices) Powder substances used with toothbrush for cleaning the surface of the teeth. Contain: 1.Soap or detergent. 2.Mild abrasive (calcium carbonate , sodium bicarbonate and sodium chloride) 3.Anticariogenic agents 4.Sweeteners and flavoring agents. 2-Powders to be dissolved in water before use Examples A. Antacids and laxatives (large dose) are used by mixing the directed amount of powder (usually one teaspoonful) in a portion of water before swallowing. B-Dietary/Food supplements. C-Douche powders.  3-Powders requiring reconstitution A. Oral antibiotic suspension 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).  B. Powders for injection Injections of medicaments that are unstable in solution must be made immediately prior to use and are presented as sterile powders in ampoules. Sufficient diluents ,e.g. sterile water for Injection ,is added from a second ampoule to produce the required drug concentration and the injection is used immediately.  Divided Powders Divided powders are dispensed in the form of individual doses (separately wrapped). They are dispensed in papers (properly folded),metal foil , small heat-sealed plastic bags , sachet or other containers.  Commercially available divided dose powders can be dispensed in: Paper packets Sachets Aerosols  paper packets White glazed paper Moisture resistance Double wrapping  Problems encountered in powder formulation (can’t be packed in paper packets) 1- Hygroscopic and Deliquescent Powder Hygroscopic powders: Powders that absorb moisture from the atmosphere and become moist (wet). Deliquescent powders: Powders absorb moisture from the atmosphere to the extent that they go into solution.  Solution: a. Reduce the amount of surface area exposed to the moisture. b. Packed in aluminum foil or in plastic film packets. c. Addition of adsorbent materials such as starch. (e.g. ammonium chloride , ammonium citrate). 2. Effervescent powders: The presence of moisture will promote the effervescent interaction resulting in preparation that cannot be used.  Solution: 1.Dispensed in granular form → reduce surface area of particles exposed to air. 2. Protect from moisture (should be double wrapped in humid weather ,further wrapping in aluminum foil or plastic cover is advisable). 3. Efflorescent powders - is the loss of water (or a solvent) of crystallization from a hydrated or solvated salt to the atmosphere on exposure to air.  Problem: Crystalline substances which during storage lose their water of crystallization. The liberated water convert the powder to a paste or to a liquid.  Solution: Using the anhydrous form + treating it in a manner similar to hygroscopic powders ( include drying bulky powder) 4. Volatile substances: Powders containing volatile oils (menthol and essential oils) → the volatile material will volatilize.  Solution Double wrapping , inner wrapper of which should be of wax paper.  Sachets Used for large scale productions (industrial). Sachets are used for unit dose dispensing of powders which are then reconstituted with water or another juice or soft food. The pack is an ideal single-dose system formed from laminated foil.  Granules Are the solid dosage form composed of powder particles that aggregate to form agglomerates of large free- flowing particles. They are irregularly shaped but may be prepared to be spherical. Particle size ranging from 2-4 mm diameter.  Reasons For Granulation 1.Prevent segregation of the constituents of the powder mix. Segregation is due to differences in the size or density of the components of the mix, the smaller and/ or denser particles concentrating at the base of a container with the larger and/ or less dense ones above them. 2.To improve the flow properties of the powder mix. Many powders, because of their small size, irregular shape or surface characteristics, are cohesive and do not flow well. 3.To improve the compaction characteristics of powder mix. Granules are often more easily compacted than powders and produce stronger tablets. 4.Reduce the hazard of toxic dust powders The granulation of toxic materials will reduce the hazard of generation of toxic dust, which may arise during the handling of the powders. 5.Reduce the hazard of hygroscopic powder adhesion Materials, which are slightly hygroscopic, may adhere & form a cake if stored as a powder  Advantages of granules over other dosage forms: 1. More stable than powders against humidity and atmosphere (Due to less exposed surface area compared to powders). They are also more stable than liquids (because chemical reactions take place more rapidly when the drug in liquid dosage forms than in solid form). 2. Faster therapeutic action than tablets and capsules, as granules do not require disintegration before the drug dissolves. 3. More flowable than powders  more uniform dosing, so, they are more preferred in compressing into tablets or filling into capsules than powders. 4. More suitable for administration of drugs with large doses (1-5 gm) that are hard to be taken as single dose tablet or capsule.  Disadvantages of granules over other dosage forms: 1. Cannot mask the taste of bitter, nauseous, and unpleasant drugs. 2. bulky to carry than tablets and capsules. Modern unit- dose granule packaging made them convenient to be carried. 3. In bulk oral granules, dose variation could happen due to different spoon sizes (except when unit packed).  Methods of granulation 1. Wet granulation: Most widely used method. involves the addition of a binder to the powder to form wet mass. Used when: For the products not degraded by moisture or heat. Wet granulation Addition of binder: It may be in the form of: Solution of PVP Paste (starch in hot water) Solvent used should be volatile and non toxic. Solvent (with or without a binder convert powder into a wet mass). Advantages of wet granulation: Large number of materials can be granulated by this method. Higher quality granules are produced by this method. Good content uniformity. Wide range of excipients can be used. Disadvantages of wet granulation: Large number of equipment are required. Time consuming and high cost.  Methods of granulation 2. Dry granulation:  It is the process in which granules are formed by the application of pressure.  Forming granules without moisture requires compacting and densifying the powders. Used when: For materials sensitive to heat and moisture.  Effervescent granules They are granules of drug in a dry mixture of Citric acid, Tartaric acid and Sodium bicarbonate. Before administration, they are added to water → the acids and the base react to liberate CO2, resulting in effervescence and the mixture should be taken while effervescing.  Advantages of effervescent granules: 1. Attractive dosage form for the public. 2. The resulting carbonated solution mask the undesirable taste of drugs. 3. The liberated CO2 gas is used as a therapeutic agent → it increases gastric secretions and hence facilitates digestion. Disadvantages of effervescent granules: 1.Instability in presence of moisture. 2.Problems in packaging and storage.