Pharmaceutical Technology II المرحلة الثالثة PDF

‫لجنة عمداء كليات الصيدلة‬ ‫لجنة توحيد منهاج مادة )‪(Pharmaceutical Technology II‬‬ ‫‪Pharmaceutical Technology II‬‬ ‫المرحلة الثالثة‬ ‫‪2024‬‬ ‫‪1‬‬ ‫التقويم لكليات الصيدلة‬ ‫ي‬ ‫تم اعداد ومراجعة...

‫لجنة عمداء كليات الصيدلة‬ ‫لجنة توحيد منهاج مادة )‪(Pharmaceutical Technology II‬‬ ‫‪Pharmaceutical Technology II‬‬ ‫المرحلة الثالثة‬ ‫‪2024‬‬ ‫‪1‬‬ ‫التقويم لكليات الصيدلة‬ ‫ي‬ ‫تم اعداد ومراجعة هذا المنهج الموحد لالمتحان‬ ‫كببة‬ ‫خبة ر‬ ‫رن‬ ‫متخصصي لديهم ر‬ ‫اس ‪ 2024-2023‬من قبل اساتذة‬ ‫للعام الدر ي‬ ‫ن‬ ‫ن‬ ‫االكاديم ‪.‬لقد بذل االساتذة قصارى جهودهم يف جمع‬ ‫ي‬ ‫والعمل‬ ‫التدريس‬ ‫ف‬‫ي‬ ‫يسبة عىل‬‫المعلومات وحرصوا عىل ترتيبها وتنظيمها لتكون واضحة و ر‬ ‫الطلبة‪.‬نأمل من طلبتنا االعزاء االستفادة من هذا المنهج ن يف طريقهم اىل‬ ‫النجاح والتفوق ‪ ،‬وهللا الموفق‪.‬‬ ‫‪2‬‬ Disperse Systems Emulsions Chapter 14 ANSEL'S Pharmaceutical Dosage Forms and Drug Delivery Systems Eleventh Edition Objectives: After reading this topic, the student will be able to: Define the pharmaceutical emulsions Distinguish between the different types of pharmaceutical emulsions based on their physical state Differentiate between the different types of pharmaceutical emulsions based on their intended uses. Compare and contrast emulsification theories: surface tension, oriented wedge, and Interfacial film. Compare and contrast various types of emulsifying agents Identify the methods and techniques employed in preparing of stable pharmaceutical emulsions. Identify the factors that affect the stability of emulsion, such as temperature and environmental conditions. 3  ‫يتكون من سائلني‬ ‫غير ممتزجني‬ Emulsions ‫واحد‬ Emulsion is a thermodynamically unstable disperse system consisting of ‫يذوب‬ two immiscible liquids, one of which is distributed throughout the other in ‫بالثاني ع‬ minute globules (droplets). ‫شكل‬ -In emulsion terminology, the dispersed phase is the internal phase, and the ‫قطرات‬ dispersion medium is the external or continuous phase. Generally, to prepare a stable emulsion, a third phase, an emulsifying agent, is necessary. ‫ مستقر الزم اجيب‬emulsio ‫لتحضير‬ ‫مادة ثالثه تعادل او تجانس‬ Internal phase Emulsifying agent Emulsion Types inter External phase 1. Oil-in-Water (o/w) Emulsions: ‫زيتي‬ - In o/w emulsions, the internal phase consists of an oleaginous or oily component, dispersed within an aqueous external phase. 2. Water-in-Oil (w/o) Emulsions: -In w/o emulsions, the internal phase consists of water or an aqueous component, dispersed within an oleaginous external phase. Because the external phase of an emulsion is continuous. An o/w emulsion may be diluted or extended with water or an aqueous preparation and a w/o emulsion, with an oleaginous or oil-miscible liquid. 3. Multiple emulsions: Multiple emulsions have multiple layers of dispersed and continuous phases, including both oil-in-water-in-oil (o/w/o) and water-in-oil-in-water (w/o/w) structures. W/O/W O/W/O 4 ‫ يمكن تخفيف أو تمديد املستحلب باملاء أو‬.‫ألن الطور الخارجي للمستحلب مستمر‬.‫ مع سائل زيتي أو سائل قابل لالمتزاج بالزيت‬،‫بمستحضر مائي ومستحلب بدون ماء‬ Macroemulsions vs. Microemulsions Microemulsions can be formed spontaneously by agitating oil and water phases with carefully selected surfactants. - The type of microemulsion produced depends on the properties of the oil and surfactants used. - Microemulsions have significantly smaller droplets compared to macroemulsions, with diameters ranging from 100 Å to 1,000 Å. - In contrast, macroemulsions have larger droplets, around 5,000 Å in diameter. - Both o/w (oil-in-water) and w/o (water-in-oil) microemulsions can be formed based on the oil and surfactant properties. Microemulsions offer advantages in oral drug delivery, providing more rapid and efficient absorption compared to solid dosage forms. Microemulsions enhance transdermal drug delivery by facilitating increased diffusion into the skin. -The small droplet size of microemulsions promotes efficient absorption through the skin barrier Macroemulsion Microemulsion Size: around 5,000 Å Size: 100 Å to 1,000 Å White opaque appearance Cloudy –Translucent or ‫معتم‬ Transparent Thermodynamically unstable Thermodynamically stable Requires a substantial input energy Forms spontaneously for production Determination tests of the emulsion type 1. Miscibility test o/w emulsion remain stable upon dilution with water, but will not remain homogenous upon addition of oil and vice versa 2. Staining test Addition of oil soluble stain to the emulsion of unknown type on a glass slide under microscope Staining globules and colorless medium= o/w emulsion Staining background and colorless globules = w/o emulsion 3. Conductivity test Water conduct electricity, hence an emulsion in which water forms the continuous phase acts as a conductor. Oil is a non-conductor and emulsion in which forms the external phase act as non-conductor. W /O non_condutor 5 O/W Condater  Classification of emulsions according to the physical state Emulsions can be formulated as: -Liquid -Semisolids According to the route of administration Based on the constituents and the intended application - Liquid emulsions may be employed: Orally: o/w for example, castor oil emulsion ‫مستحلب زيت الخروع‬ Topically: for example lotion Parenterally: (I.V. o/w ) (I.M. and S.C. may be w/o) - Semisolid emulsions ‫املراهم‬ Topically: for examples, lotions, creams and liniments The choice between o/w and w/o emulsions depends on many factors such as: 1- The nature of therapeutic agents, 2- Desired effects, 3- The intended route of administration Purpose and Benefits of Emulsions Improved Drug Administration: Emulsification allows the pharmacist to create stable mixtures of two immiscible liquids, enabling the administration of a liquid drug in the form of minute globules (introducing of many ingredients in different phases as liquid dosage form). ‫يمكن‬ - Orally administered emulsions, are always in the form of o/w ‫اخفي‬ ‫الطعم املر‬ emulsions. They can improve the palatability of drug administration by ‫بأظافة‬ dispersing it in a sweetened, flavored aqueous vehicle (taste masking). ‫عوامل‬ o/w emulsion act as carrier for lipophilic drugs, enabling the oil soluble ‫محلية‬ drug to dissolved in the dispersed phase and potentially enhance oral bioavailability -Sterile I.V. o/w emulsions are used for administration of nutritive oil and oil soluble vitamins to the patients unable to ingest food. Intravenous emulsions must be o/w. -Intramuscular and subcutaneous injections can be formulated as w/o emulsions. In such oily emulsions, the drug's effects are prolonged, as the drug must diffuse from the aqueous dispersed phase through the external oil phase to reach the tissue fluids. ‫التاثير يكون اطول‬ 6 -Emulsions for topical use can be either o/w or w/o, depending on the nature of therapeutic agents, the desired effects, and skin conditions. - An o/w emulsion is more easily removed from the skin with water, making it suitable when easy removal is required. Medicinal agents that irritate the skin generally are less irritating in the internal phase of an emulsified topical preparation than in the external phase. - w/o emulsions are more softening to the skin, resisting drying and removal by contact with water. ‫تقلص‬ - The diminished particle size of the internal phase in emulsions can enhance percutaneous absorption (absorption through the skin), making them a valuable choice for dermatological formulations. The acceptable emulsion is characterized by the following: 1. The globules of dispersed phase must be remain uniformly distributed throughout the continuous phase 2. The formulation should have a pleasing appearance and texture 3. For oral administration, the flavor must be appropriate 4. For external application, the formulation must be easily spread over the affected area 5. Physically stable (shows no signs of flocculation, creaming, sedimentation and coalescence) 6. Absence of deterioration by microorganisms Disadvantages of emulsions 1. Pharmaceutical emulsions, being thermodynamically unstable, require careful formulation to prevent the separation of their two phases. 2. Before measuring a dose, it is essential to shake the emulsion thoroughly. Even with efficient shaking, the accuracy of the dose is likely to be lower compared to solutions. 3. Storage conditions may affect the disperse system, potentially causing creaming or cracking 4. There is a possibility of microbial contamination, which can further lead to cracking issues 5. In comparison to solid dosage forms, liquid dosage forms, such as emulsions, tend to be more bulky Gibbs free energy in an emulsion ΔG = ΔA γ A is the total surface area of dispersed particles γ is the interfacial tension , 7 ‫الضغط الداخلي‬  ‫ عالقة طرديه‬G ‫ و‬ŷ ‫عالقة‬ ‫ صغيرة‬G ‫ كبيرة و‬A ‫الزم تكون‬ Expulsion Stable emulsions must have a large “A” and a small “G” concurrently for consistent and uniform dosing. This is done by decreasing “γ,” which will decrease “G,” which will decrease self-attraction of dispersed phase particles ‫؟‬stable emulsion ‫شلون اعرف عندي‬ Theories of Emulsification ‫ صغيرة‬y ‫اذا كانت املساحه كبيرة و‬ There are many theories of emulsification: 1. Surface Tension Theory: All liquids tend to minimize their surface area by forming spherical shapes, which is the shape with the least surface area. Surface tension measures this tendency and is a force that resists the formation of smaller droplets when two immiscible liquids come into contact. - Emulsifying agents, often called surfactants or wetting agents, reduce interfacial tension and diminish the liquids' attraction to their own molecules (reducing the repellent force between the liquids and diminishing each liquid's attraction for its own molecules). - This theory suggests that emulsifiers lower the interfacial tension between immiscible liquids, thus, the surface-active agents facilitate the breaking up of large globules into smaller ones, which then have a lesser tendency to reunite or coalesce 2. Oriented-Wedge Theory: - This theory is based on the idea that emulsifying agents form monomolecular layers around the droplets of the internal phase. The theory is based on the assumption that certain emulsifying agents orient themselves about and within a liquid in a manner reflective of their solubility in that particular liquid. - In a system containing two immiscible liquids, probably the emulsifying agent is preferentially soluble in one of the phases and is embedded more deeply in that phase than the other. Because many molecules of substances have a hydrophilic or water-loving portion and a hydrophobic or water- hating portion, the molecules position or orient themselves into each phase. - Emulsifying agents with a greater hydrophilic character tend to promote o/w emulsions, while those with a more hydrophobic character favor w/o emulsions. - The phase in which the emulsifier is more soluble becomes the continuous phase of the emulsion. ‫تصبح املرحلة التي يكون فيها املستحلب أكثر قابلية للذوبان هي املرحلة املستمرة للمستحلب‬ 8 3. Plastic or Interfacial Film Theory: This theory places emulsifying agents at the interface between the immiscible liquids, forming a thin film adsorbed on the surface of internal phase droplets. - The film acts as a barrier, preventing contact and coalescence of the dispersed phase. - The stability of the emulsion depends on the toughness and flexibility of this film. - The degree of solubility of the emulsifying agent in the two phases determines whether o/w or w/o emulsions are formed. Preparation of Emulsions Factors Affecting Emulsion Formation: The stability and characteristics of an emulsion are influenced by the following factors: - Emulsifying agents -pH -The ratio of internal to external phases. The success of emulsions depends on the careful selection of emulsifying agents and understanding their properties. The initial step in preparation of an emulsion is selection of the emulsifier. ‫اختيار‬ Criteria for Selecting Emulsifying Agents: :‫معايير اختيار عوامل االستحالب‬ 1. Compatibility: Emulsifying agents must be compatible with other formulation ingredients and should not interfere with the stability or efficacy of the therapeutic agent. 2. Stability: Emulsifying agents should be stable and not deteriorate during the preparation or storage of the pharmaceutical product. 3. Safety: Emulsifiers should be nontoxic and safe for consumption by the patient, and they should possess minimal odor, taste, or color. 4. Promotion of Emulsification: A crucial role of emulsifying agents is to promote emulsification, ensuring that the two immiscible phases are dispersed effectively. 9  Common Types of Emulsifying Agents 1. Carbohydrate Materials: - Naturally occurring agents like acacia, tragacanth, agar, chondrus, and pectin are used. These materials form hydrophilic colloids. They typically form o/w emulsions. - Acacia is often used in extemporaneous emulsions. Tragacanth and agar are commonly employed as thickening agents in acacia-emulsified products. ‫مادة تستخدم‬ ‫في العديد من‬ Microcrystalline cellulose is employed in a number of commercial ‫االدويه تسوي‬ emulsions as a viscosity regulator. ‫لزوجه‬ 2. Protein Substances: - Gelatin, egg yolk, and casein are examples of protein-based emulsifiers that produce o/w emulsions. - Gelatin, while effective, can lead to emulsions that become more fluid over time. 3. Molecular Weight Alcohols: - Substances like stearyl alcohol, cetyl alcohol, and glyceryl monostearate are primarily used as thickening agents and stabilizers for o/w emulsions in external applications. -Cholesterol and cholesterol derivatives may also be employed in externally used emulsions to promote w/o emulsions 4. Wetting Agents: - These agents can be anionic, cationic, or nonionic and contain both hydrophilic and lipophilic groups. In anionic agents, the lipophilic portion is negatively charged, but in the cationic agent, it is positively charged. - Anionic and cationic agents tend to neutralize each other and are considered incompatible, while nonionic emulsifiers show no inclination to ionize. Depending on their individual nature, certain members of these groups form o/w emulsions and others w/o emulsions. ‫احادي التكافؤ‬ ‫متعدد التكافؤ‬ -Anionic emulsifiers include various monovalent, polyvalent, -Organic soaps, such as triethanolamine oleate, ‫الصابون العضوي‬ 10 - Sulfonates, such as sodium lauryl sulfate. - Cationic emulsifier, such as Benzalkonium chloride (known primarily for its bactericidal properties) -Nonionic emulsifiers, such as span and tween 5. Finely Divided Solids: - Colloidal clays like bentonite, magnesium hydroxide, and aluminum hydroxide can form o/w emulsions when the insoluble material is added to the aqueous phase if there is a greater volume of the aqueous phase than of the oleaginous phase. If the powdered solid is added to the oil and the oleaginous phase volume predominates, a substance such as bentonite is capable of forming a w/o emulsion. - The relative volume of internal and external phases is critical for their effectiveness. ‫مساعد‬ Auxiliary emulsifying agent - Lipophilic -High molecular Weight Alcohols Substances like stearyl alcohol, cetyl alcohol, and glyceryl monostearate are primarily used as thickening agents and stabilizers for o/w emulsions in external applications. - Hydrophilic Tragacanth and agar are commonly used as thickening agents in acacia – emulsified products Mechanisms of action of emulsifying agents Type Example Mechanism Mono-molecular Potassium laureate Coherent flexible film Tween 80 formed by SAA. (Lower interfacial tension) and stabilize the emulsion Multi-molecular Acacia, Gelatin Strong rigid film formed mostly by hydrocolloids, which produce O/W emulsions. Stability due mainly to strength of interfacial film (forming a coherent multi-molecular film which is strong and prevent the coalescence) Solid particles Bentonite Film formed by solid Magnesium hydroxide particles that are small in size compared to the droplets of the dispersed state Particles wetted by both phases to some extent in order to remain at the interface and form a stable film (form a particulate film that prevent the coalescence) 11  Hydrophilic-Lipophilic Balance (HLB) System: Generally, each emulsifying agent has a hydrophilic portion and a lipophilic portion, with one or the other being more or less predominant and influencing in the manner already described the type of emulsion. A method has been devised whereby emulsifying or surface-active agents may be categorized on the basis of their chemical makeup as to their hydrophilic-lipophilic balance, or HLB. ‫لكل ماده‬ By this method, each agent is assigned an HLB value or number indicating HLB ‫معني‬ the substance's polarity (the numbers have been assigned up to about 40). The usual range is between 1 and 20. Each surfactant have an HLB number representing the relative proportions of the lipophilic and hydrophilic parts of the molecule -Materials that are highly polar or hydrophilic have been assigned higher ‫كل ما كان الرقم من‬ numbers than materials that are less polar and more lipophilic. ‫ اكبر‬20 ‫ الى‬1 ‫معناها يحب املاء‬ Materials with HLB values of 3 to 6 are highly lipophilic and favor water- ‫واذا اقل يعني كارهه‬ in-oil (w/o) emulsions. ‫للماء‬ - HLB values of about 8 to 18 correspond to emulsifying agents favoring oil-in-water (o/w) emulsions. Activity Assigned HLB Antifoaming 1-3 Emulsifiers (w/o) 3-6 Wetting agents 7-9 Emulsifiers (o/w) 8-18 Solubilizers 15-20 Detergents 13-16 Required HLB To ensure emulsion stability, it is necessary to select emulsifying agents having the same or nearly the same HLB value as the oleaginous phase of the intended emulsion. Certain emulsifying agents of a given HLB value appear to work best with a particular oil phase and this has given rise to the concept required HLB value for any oil or combination of oils. All oils, waxes and other materials likely to be incorporated into emulsions have an individual "Required HLB." 12 For example, mineral oil has an assigned HLB value of 4 if a w/o emulsion is desired and a value of 10.5 if an o/w emulsion is to be prepared. To prepare a stable emulsion, the emulsifying agent should have a required HLB value similar to the one for mineral oil, depending on the type of emulsion desired. Hydrophilic-lipophilic balance (HLB) method is used for calculating the HLB ‫نستخدم‬ ‫حتى نحسب‬ relative quantities of SAA (emulgents) that necessary for producing a SAA physically stable emulsion. Blending Emulsifying Agents and Calculations in the HLB System: Stability is achieved by selecting emulsifying agents with HLB values similar to the intended emulsion. ‫مرات احتاج‬ ‫اخبط اكثر من‬ Combining two or more emulsifiers may be necessary to achieve the emulsifiers required HLB value. ‫حتى اوصل لل‬ ‫ املناسب‬HLB HLB values are additive, allowing the blending of surfactants to achieve the desired total HLB value. The HLB of a mixture of surfactants, for example, a mixture consisting of A and B surfactants Total =1 If fraction A = x Then fraction B = 1-X Total HLB= fraction A ( x) + fraction B (1 - x) Calculation the HLB for a mixture of surfactants is assumed to be an algebraic summation of the two HLB numbers 1. Multiply the HLB of each surfactant by its fraction. 2. Add the obtained values to get the total HLB Total HLB = HLBA ( X) + HLBB (1-X) - Example: In the Blending two surfactants, what is the ratio of each surfactant? Surfactant A with an HLB value of 8.0, surfactant B with an HLB value of 12.0 to achieve a total HLB value of 9.0. If fraction A = x Then fraction B = 1-X Total HLB = HLBA ( X) + HLBB (1-X) 13 9 = 8( X) + 12(1-X) Fraction A = X= 0.75 Fraction B =1-X = 1- 0.75 =0.25 ( 3: 1) -Example: A formulator is required to formulate an o/w emulsion of the basic formula : Liquid paraffin 50 g Emulsifying agents (required HLB 10.5) 5g Water to 100 g Calculate the fraction of Tween 80 (HLB of 15) and Span 80 (HLB of 4.3) used to produce a physically stable liquid paraffin emulsion. If fraction of tween 80 =X HLB ‫قيمة ال‬ ‫هي التي تحدد‬ Then fraction of span 80 =1-X ‫هل محب‬ ‫للدهون او محب‬ HLB mixture = HLBA ( X) + HLBB (1-X) ‫للماء‬ 10.5 =15 * (x) + 4.3 *(1-x) X=0.58 fraction of A ( tween 80) 1-0.58=0.42 fraction of B ( span 80) 0.58* 5 g = 2.9 g of tween 80 0.42 * 5 g = 2.1 g of span 80 Example: o/w Emulsion Liquid petrolatum (Required HLB 10.5) 50 g Emulsifying agents 5g Sorbitan monooleate (HLB 4.3) Polyoxyethylene 20 sorbitan monoleate (HLB 15.0) Water qs 100 g By simple algebra, it can be shown that 4.5 parts by weight of sorbitan monooleate blended with 6.2 parts by weight of polyoxyethylene 20 sorbitan monooleate will result in a mixed emulsifying agent having the required HLB of 10.5. Because the formula calls for 5 g, the required weights are 2.1 and 2.9 g, respectively. The oil-soluble sorbitan monooleate is dissolved in the oil and heated to 75°; the water-soluble 14 polyoxyethylene 20 sorbitan monooleate is added to the aqueous phase that is heated to 70°. At this point, the oil phase is mixed with the aqueous phase and the whole is stirred continuously until cool. The formulator is not restricted to these two agents to produce a blend with an HLB of 10.5. There are various proportions required, using other pairs of emulsifying agents, Preparation Methods Various methods are employed for emulsion preparation, ranging from small-scale laboratory techniques to large-scale industrial processes. Each method has its advantages and is chosen based on the nature of components and desired emulsion characteristics 15 Small-Scale Emulsion Preparation Methods -Laboratory Equipment: Small-scale emulsions can be prepared using equipment like: 1. Dry Wedgwood or porcelain mortar and pestle, 2.Mechanical blenders such as milkshake mixers, hand homogenizers, or 3. Simple prescription bottles. Laboratory Homogenizers -Laboratory Techniques: In the small-scale extemporaneous preparation of emulsions, three methods may be used. They are: 1. The continental or dry gum method 2. The English or wet gum method 3. The bottle or Forbes bottle method -The continental or dry gum method: ‫مانستخدم بها ماء‬ The continental or dry gum method involves triturating the emulsifying agent (e.g., acacia) with oil before adding water (addition of external phase to the internal phase). The continental method is also referred to as the 4:2:1 method because for every four parts by volume of oil, two parts of water and one part of gum are added in preparing the initial or primary emulsion. For instance, if 40 mL of oil is to be emulsified, 20 mL of water and 10 g of gum would be employed in the primary emulsion. In this method, the acacia or other o/w emulsifier is triturated with the oil in a perfectly dry Wedgwood or porcelain mortar until thoroughly mixed. After the oil and gum have been mixed, the two parts of water are added all at once, and the mixture is triturated immediately, rapidly, and continuously until the primary emulsion is formed. A mortar with a rough rather than smooth inner surface must be used to ensure proper grinding action and reduction of the globule size. A glass mortar is too smooth to produce the proper reduction of the internal phase. 16  The emulsion is transferred to a graduate and made to volume with water previously swirled about in the mortar to remove the last portion of emulsion. -English or Wet Gum Method: The English or wet gum method creates a mucilage of the emulsifying agent with water before slowly incorporating oil (addition of internal phase to the external phase). By this method, the same proportions of oil, water, and gum are used as in the continental or dry gum method, but the order of mixing is different. A mucilage of the gum is prepared by triturating in a mortar granular acacia with twice its weight of water. The oil is then added slowly in portions, and the mixture is triturated to emulsify the oil. After all of the oil has been added, the mixture is thoroughly mixed for several minutes to ensure uniformity. Then, the other formulative materials are added, and the emulsion is transferred to a graduate and brought to volume with water. -Bottle or Forbes bottle method: The bottle or Forbes bottle method is suitable for volatile oils or oleaginous substances of low viscosities, involving shaking the mixture in a capped bottle. Powdered acacia is placed in a dry bottle, two parts of oil are added, and the mixture is thoroughly shaken in the capped container. A volume of water approximately equal to that of the oil is then added in portions and the mixture thoroughly shaken after each addition. When all of the water has been added, the primary emulsion thus formed may be diluted to the proper volume with water or an aqueous solution of other formulative agents Important considerations on emulsion preparation ‫قبل‬ ❖ Prior to mixing, all the water soluble ingredients are dissolved in the aqueous phase and all the oil-soluble components are dissolved in the oil ❖ Solid substances such as preservatives, stabilizers, colorants, and any flavoring material are usually dissolved in a suitable volume of water (assuming water is the external phase) and added as a solution to the primary emulsion. ❖ If fats waxes or SAA that are solids or semisolid at room temperature are needed, warm the two phases, the aqueous phase temperature is raised 2-3C° above that of oil phase, so that no local crystallization of waxes takes place upon mixing of the two phases 17  ❖ Any substances that might interfere with the stability of the emulsion or the emulsifying agent are added as near last as is practical. ❖ Alcohol has a precipitating action on gums such as acacia, thus no alcohol or solution containing alcohol should be added directly to the primary emulsion, because the total alcoholic concentration of the mixture would be greater at that point than after other diluents were added. ❖ When all necessary agents have been added, the emulsion is transferred to a graduate and made to volume with water previously swirled about in the mortar to remove the last portion of emulsion. ❖ Forbes bottle method is not suited for viscous oils because they ‫منكدر‬ ‫نستخدمها‬ cannot be thoroughly agitated in the bottle when mixed with the ‫للمراد اللزجه‬ emulsifying agent. ❖ When the intended dispersed phase is a mixture of fixed oil and volatile oil, the dry gum method is generally employed Auxiliary Methods: An emulsion prepared by either the wet gum or the dry gum method can generally be increased in quality by passing it through a hand homogenizer. In this apparatus, the pumping action of the handle forces the emulsion through a very small orifice that reduces the globules of the internal phase to about 5 j.lm and sometimes less. The hand homogenizer is less efficient in reducing the particle size of very thick emulsions. In Situ Soap Method (Nascent soap method): The two types of soaps developed by this method are calcium soaps and soft soaps. Calcium soaps are w/o emulsions that contain certain vegetable oils, such as oleic acid, in combination with limewater (Calcium Hydroxide Solution, USP). They are prepared simply by mixing equal volumes of the oil and limewater. The emulsifying agent in this instance is the calcium salt of the free fatty acid formed from the combination of the two entities. In the case of olive oil, the free fatty acid is oleic acid, and the resultant emulsifying agent is calcium oleate. Large-scale preparation On a larger scale, mixing tanks equipped with high-speed impellers are used for emulsion formation. - Colloid mills or large homogenizers may be employed to refine the emulsion further. Industrial homogenizers have the capacity to handle as much as 100,000 L of product per hour. 18 Stability of Emulsions The instability of emulsions can be categorized as follows: 1-. Flocculation 2. Creaming or sedimentation 3. Coalescence or aggregation 4. Cracking or breaking 5. Phase separation -Flocculation This process refers to aggregation or joining droplets together (without any change in primary droplet size) to form a large units or clumps ( floccules) which rise or settle in the emulsion depending on their densities. Good emulsion Flocculation -Creaming Aggregates of globules of the internal phase have a greater tendency than do individual particles to rise to the top of the emulsion or fall to the bottom. Such a preparation of the globules is termed the creaming of the emulsion, it is a reversible process. Creamed emulsion can be restored to its original state by gentle agitation, if insufficient shaking is employed before each dose, improper dosage of the internal phase substance may result. According to the Stokes equation the rate of separation of the dispersed phase of an emulsion may be related to such factors: 1. The particle size of the dispersed phase, 2. The difference in density between the phases, 3. The viscosity of the external phase. -Larger particle size, greater density difference, and lower viscosity increase the rate of creaming. 19 Upward creaming takes place in unstable emulsions of the o/w or the w/o type in which the internal phase has a lesser density than the external phase. Downward creaming takes place in unstable emulsions in which the opposite is true Creaming Strategies for enhanced the stability: 1. The globule or particle size should be reduced as fine as is practically possible, 2. The density difference between the internal and external phases should be minimal, 3. The viscosity of the external phase should be reasonably high. -Coalescence and Breaking (Cracking) If the droplet contacts another droplet, coalescence will occur to produce a single droplet of greater diameter and, the surface area of the new droplet will be less than the surface areas of the two individual droplets. This process will continue until there is complete phase separation (i.e. two liquid layers occur). Separation of the internal phase from the emulsion is called breaking, and the emulsion is described as being cracked or broken. This is irreversible, because the protective sheath about the globules of the internal phase no longer exists. If an emulsion has cracked it cannot be recovered or redispersed by shaking. Coalescence Separation (Breaking) -Phase Inversion It is the process of an exchange between the disperse phase and the medium. For example, an o/w emulsion may with time or change of conditions invert to a w/o emulsion (occurs when the dispersed phase exceed a theoretical maximum of 74% of the total volume).. Inversion o/w emulsion w/o emulsion 20 Consideration for temperature, light, environmental factors and storage ❖ Generally, care must be taken to protect emulsions against extremes of cold and heat. Freezing and thawing coarsen an emulsion and sometimes break it. Excessive heat has the same effect. ❖ The presence of light, air, and contaminating microorganisms can adversely affect the stability of an emulsion; appropriate formulative and packaging steps are usually taken to minimize such hazards to stability. ❖ For light-sensitive emulsions, light-resistant containers are used. ❖ For emulsions susceptible to oxidative decomposition, antioxidants may be included in the formulation and adequate label warning provided to ensure that the container is tightly closed to air after each use. ‫الفطريات تاثر اكثر ع‬ Preservation of emulsion ‫اليمولشن من البكتريا‬ Many molds, yeasts, and bacteria can decompose the emulsifying agent, disrupting the system. Because fungi (molds and yeasts) are more likely to contaminate emulsions than are bacteria, fungistatic preservatives, commonly combinations of methylparaben and propylparaben, are generally included in the aqueous phase of an o/w emulsion. -Alcohol in the amount of 12% to 15% based on the external phase volume is frequently added to oral o/w emulsions for preservation. Therapeutic examples of Oral and Topical Emulsions Oral Emulsions -Mineral Oil Emulsion: - Mineral oil emulsion, or liquid petrolatum emulsion, is an o/w emulsion prepared from the following materials: Mineral oil, acacia, syrup, vanillin, alcohol, and purified water. - Preparation by the dry gum method (4:2:1). - Used as a lubricating cathartic with enhanced palatability compared to plain mineral oil. - Commercial variations may include additional cathartic agents. -Castor Oil Emulsion: - Indications: Laxative for constipation and colon preparation for diagnostic examinations. 21 - Simethicone Emulsion: - Indications: Defoaming agent for relief of gastrointestinal gas symptoms. Topical Emulsions -Lotions Many hand and body lotions for dry skin are o/w emulsions. A number of topical emulsions, or lotions, are used therapeutically to deliver a drug systemically. An example is Estrasorb, which contains estradiol for menopausal symptom relief. -Shampoos: - Shampoos are solution, emulsion, or suspension dosage forms used for hair and scalp cleansing. -Liniments Liniments are alcoholic or oleaginous solutions or emulsions of various medicinal substances intended to be rubbed on the skin The vehicle for a liniment should therefore be selected for the type of action desired (rubefacient, counterirritant, or massage) and also on the solubility of the desired components in the various solvents. All liniments should bear a label indicating that they are suitable only for external use and must never be taken internally. Liniments that are emulsions or that contain insoluble matter must be shaken thoroughly before use to ensure even distribution of the dispersed phase, and these preparations should be labeled shake well. liniments are prepared in the same manner as solutions, emulsions, or suspensions 22 Suppositories and Inserts Chapter 12 Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Eleventh Edition Objectives After reading this topic, the student will be able to : Compare and contrast various suppository and insert, in terms of physical appearance, size and shape Describe the advantages of suppositories and inserts. Identify and explain physiologic factors that influence the drug absorption from rectal suppository administration Identify and explain the physicochemical factors of the drug and suppository/insert base as these influence absorption Compare and contrast the various classes of suppository bases Describe the three methods of suppository preparation 23 Suppositories Suppositories are solid dosage forms intended for insertion into body orifices where they melt, soften, or dissolve and exert local or systemic effects. Suppositories are commonly used rectally, vaginally, and occasionally urethrally They are used to deliver both systemically and locally acting medications 24 Suppositories Shapes Suppositories have various shapes and weights. The shape and size of a suppository must be such that it can be easily inserted into the intended orifice without causing undue distension, and once inserted, it must be retained for the appropriate period. Rectal suppositories are inserted with the fingers, but certain vaginal suppositories, particularly the inserts, or tablets prepared by compression, may be inserted high in the tract with the aid of an appliance. ‫ب استخدام بعض االجهزة‬ Rectal suppositories Rectal suppositories are usually about 32 mm (1.5 in.) long, are cylindrical, and have one or both ends tapered. Some rectal suppositories are shaped like a bullet, a torpedo, or the little finger. Depending on the density of the base and the medicaments in the suppository, the weight may vary. Adult rectal suppositories weigh about 2 g when cocoa butter (theobroma oil) is employed as the base. Rectal suppositories for use by infants and children are about half the weight and size of the adult suppositories and assume a more pencil-like shape. Vaginal suppositories Vaginal suppositories, also called (in past) pessaries, are usually globular, oviform, or cone- shaped and weigh about 5 g when cocoa butter is the base. However, depending on the base and the manufacturer's product, the weights of vaginal suppositories may vary widely. Urethral suppositories Urethral suppositories, also called bougies, are slender, pencil-shaped suppositories intended for insertion into the male or female urethra. Male urethral suppositories may be 3 to 6 mm in diameter and approximately 140 mm long. Female urethral suppositories are about half the length and weight of the male urethral suppository, being about 70 mm long and weighing about 2 g when made of cocoa butter. Urethral suppositories may be: antibacterial or a local anesthetic preparative for a urethral examination. 25 Fate of the suppository Once inserted, the suppository base melts, softens, or dissolves, distributing its medicaments to the tissues of the region. These medicaments may be intended for retention within the cavity for local effects, or they may be intended to be absorbed for systemic effects. They may exhibit the effect immediately or sustain the release of the drug such as Long-acting or slow-release suppositories are also prepared. Morphine sulfate in slow-release suppositories is prepared by compounding pharmacists. The base includes a material such as alginic acid, which will prolong the release of the drug over several hours. ‫اذا اريد فعالية‬ ‫العالج اطول الزم‬ ‫اضيف‬ Local rectal suppositories Rectal suppositories intended for local action are most frequently used to relieve ‫التحاميل املستقيمية املوضعية التحاميل الشرجية املخصصة للعمل املوضعي هي األكثر استخدامًا للتخفيف‬ 1. Constipation A popular laxative, glycerin suppositories promote laxation by local irritation of the mucous membranes, probably by the dehydrating effect of the glycerin on those membranes. 26  2. The pain, irritation, itching, and inflammation associated with hemorrhoids or other anoectal conditions. Anti-hemorrhoidal suppositories frequently contain a number of components, including local anesthetics, vasoconstrictors, astringents, analgesics, soothing emollients, and protective agents. Local vaginal suppositories Vaginal suppositories or inserts intended for local effects are employed mainly as: ‫منع‬ ‫ الحمل‬1. Contraceptives, the drugs used are nonoxynol-9 ‫ مضاده للباراسايت‬2. Antiseptics in feminine hygiene, trichomonacides to combat vaginitis caused by Trichomonas vaginalis 3. Specific agents to combat an invading pathogen. Most commonly, antifungals to treat Candida (Monilia) albicans, and anti- infectives/antibiotics directed at other microorganism Systemic effect of rectal suppositories For systemic effects, the mucous membranes of the rectum and vagina permit the absorption of many soluble drugs. However, vaginal route is not frequently used for systemic purpose. The advantages of the rectal route (for systemic effects) over oral ‫فوائد التحاميل‬ ‫مقارنة ب العالج‬ therapy are: ‫عن طريق الفم‬ (a) Drugs destroyed or inactivated by the pH or enzymatic activity of the stomach or intestines need not be exposed to these destructive environment (b) Drugs irritating to the stomach may be given without causing such irritation. (c) Drugs destroyed by portal circulation may bypass the liver (partially) after rectal administration. (d) The route is convenient for administration of drugs to patients who are unable or unwilling to swallow medication. (e) It is an effective route in the treatment of patients with vomiting. Examples of drugs administered rectally for systemic effect Prochlorperazine for the relief of nausea and vomiting, indomethacin (NSAIDs) and ondansetron for the relief of nausea and vomiting Some factors affecting on drug absorption from rectal suppositories The dose of a drug administered rectally may be greater than or less than the dose of the same drug given orally, depending on such factors as: The physicochemical nature of the drug Its ability to traverse the physiologic barriers to absorption 27  The nature of the suppository vehicle and its capacity to release the drug and make it available for absorption. Rectal absorption The factors that affect rectal absorption of a drug may be divided into two main groups: (a) Physiological factors (b) Physicochemical factors of the drug and the base Physiological factors The human rectum is approximately 15 to 20 cm long. When empty of fecal material, the rectum contains only 2 to 3 mL of inert mucous fluid. (Low volume of fluid available) In the resting state, the rectum is not motile; there are no villi or microvilli on the rectal mucosa. However, there is abundant vascularization of the submucosal region of the rectum wall with blood and lymphatic vessels. ‫من اريد‬ Among the physiologic factors that affect drug absorption from the ‫امتصاص عالي‬ ‫الزم اقلل ال‬ rectum are the colonic contents, and the pH and lack of buffering colonic content capacity of the rectal fluids. Colonic Content When systemic effects are desired, greater absorption may be expected from a rectum that is void than from one that is distended with fecal matter. A drug will obviously have greater opportunity to make contact with the absorbing surface of the rectum and colon in an empty rectum. Therefore, when deemed desirable, an evacuation enema may be administered and allowed to act before the administration of a suppository of a drug to be absorbed. Other conditions, such as diarrhea, colonic obstruction due to tumorous growths, and tissue dehydration can all influence the rate and degree of drug absorption from the rectum. Circulation Route Drugs absorbed rectally, unlike those absorbed after oral administration, bypass the portal circulation during their first pass into the general circulation, thereby enabling drugs otherwise destroyed in the liver to exert systemic effects. The lower hemorrhoidal veins surrounding the colon receive the absorbed drug and initiate its circulation throughout the body, bypassing the liver. Lymphatic circulation also assists in the absorption of rectally administered drugs 28 pH and Lack of Buffering Capacity of the Rectal Fluids Because rectal fluids are essentially neutral in pH (pH 7) and have no effective buffer capacity, the form in which the drug is administered will not generally be chemically changed by the environment. The suppository base has a marked influence on the release of active constituents. While cocoa butter melts rapidly at body temperature, because of its immiscibility with fluids, it fails to release fat-soluble drugs readily. Physicochemical factors of the drug and suppository base Physicochemical factors of the drug include such properties as: 1. The relative solubility of the drug in lipid and in water and 2. The particle size of a dispersed drug, and surface properties 3. Amount of drug 4. pKa of the drug Physicochemical factors of the base include: 1. Its ability to melt, soften, or dissolve at body temperature 2. Its ability to release the drug substance 3. Its hydrophilic or hydrophobic character (composition of the base) 4. Rheological properties. Lipid-Water Solubility of drug The lipid-water partition coefficient of a drug is an important consideration in the selection of the suppository base and in anticipating drug release from that base. A lipophilic drug that is distributed in a fatty suppository base in low concentration has less tendency to escape to the surrounding aqueous fluids than a hydrophilic substance in a fatty base. Water soluble bases—for example, polyethylene glycols—that dissolve in the anorectal fluids release for absorption water-soluble and oil-soluble drugs. 29  Drug solubility and suppository formulation Solubility of drug in Fat Water Choice of base Low High Fatty base High Low Aqueous base Low Low Intermediate ‫اذا زادت‬ ‫ يصير‬Amount of drug ‫ امتصاص‬Naturally, the more drug a base contains, the more drug will be available ‫ اكثر‬for absorption. However, if the concentration of a drug in the intestinal lumen is above a particular amount, which varies with the drug, the rate of absorption is not changed by a further increase in the concentration of the drug. ‫اذا قل‬ Particle Size ‫الحجم‬ For un-dissolved drugs in a suppository (suspension), the size of the drug ‫يزداد‬ ‫االمتصاص‬ particle will influence its rate of dissolution and its availability for absorption. The smaller the particle, the greater the surface area, the more readily the dissolution of the particle and the greater the chance for rapid absorption. Nature of the Base The base must be capable of melting, softening, or dissolving to release its drug for absorption. If the base interacts with the drug to inhibit its release, drug absorption will be impaired or even prevented. Also, if the base irritates the mucous membranes of the rectum, it may initiate a colonic response and prompt a bowel movement, eliminating the prospect of complete drug release and absorption. Because of the possibility of chemical and/or physical interactions between the medicinal agent and the suppository base, which may affect the stability and/or bioavailability of the drug, the absence of any drug interaction between the two agents should be ascertained before or during formulation. Properties of the ideal suppository base 1. Non-toxic, non- irritating to sensitive and inflamed tissues. 2. Inert and compatible with medicaments. ‫خامل‬ 30 3. Not deteriorated or contaminating the drug during storage. 4. Easily manufactured by compression or molding. 5. Dissolve or disintegrate in mucous secretions or melt quickly at body temperature to allow the release of medicament. 6. Remain molten for a sufficient period of time to allow pouring into molds. 7. Solidify rapidly to minimize sedimentation of dispersed solids. 8. Contract on cooling to allow easy withdrawal of the suppository from the mold. 9. Has wetting and emulsifying properties. 10. Stable on storage, keeps its shape during storage or handle (does not change color, odor and drug release pattern). Suppository bases Requisites for a suppository base is that it should remain solid at room temperature but soften, melt, or dissolve readily at body temperature so that the drug is fully available soon after insertion. Main types of suppository bases: 1. Fatty bases or oleaginous bases, Cocoa butter (theobroma oil) melts quickly at body temperature, but is immiscible with body fluids as for fat-soluble drugs tend to remain in the oil and have little tendency to enter the aqueous physiologic fluids. ‫تفضل‬ ‫استعماله‬ For water- soluble drugs in cocoa butter, the reverse is usually true and ‫بحالة‬ ‫االلتهابات‬ good release results. Also, when irritation or inflammation is to be relieved, ‫الن هو دهن‬ as in the treatment of anorectal disorders, cocoa butter appears to be the superior base because of its emollient or soothing, spreading action 2. Water soluble or water miscible bases, glycerinated gelatin or polyethylene glycol, Fat-soluble drugs seem to be released more readily from these bases, but both of which dissolve slowly in body fluids. 3. Miscellaneous bases, generally combinations of lipophilic and hydrophilic substances. Fatty or Oleaginous Bases 1. Cocoa butter 2. Hydrogenated fatty acids of vegetable oils, such as palm kernel oil and cotton seed oil. 3. Fat-based compounds, esters of glycerin with the higher-molecular- weight fatty acids, such as palmitic and stearic acids, such as glyceryl monostearate and glyceryl monopalmitate. 31  ‫اي شي بي‬ fat ‫يعني‬triglycerinfat fat soluble ‫او‬ The bases in many commercial products employ varied combinations of these types of materials to achieve the desired hardness under conditions of shipment and storage and the desired quality of submitting to the temperature of the body to release their medicaments. Cocoa Butter, NF Are fat obtained from the roasted seed of Theobroma cacao. At room temperature, it is a yellowish-white solid having a faint, agreeable chocolate-like odor (naturally occurring comp.) Chemically, the main constituent of cocoa butter is the triglyceride derived from palmitic acid, stearic acid, and oleic acid, primarily of oleo- palmito-stearin and oleo-distearin Cocoa butter melts at 30°C to 36°C, it is an ideal suppository base, melting just below body temperature and yet maintain in its solidity at usual room temperature. However, because of its triglyceride content, cocoa butter exhibits marked polymorphism, or existence in several crystalline forms Cocoa Butter polymorphism ‫حرارة كلش مرتفعه‬ When cocoa butter is carelessly melted at a temperature greatly exceeding the minimum required temperature (about 35°C) and is then quickly chilled, the result is a metastable crystalline form (alpha crystals) with a melting point much lower than that of the original cocoa butter (melts at ‫غير‬ ‫مستقره‬ 22°C). However, because the crystalline form is a metastable condition, there is a slow transition to the more stable beta form of crystals having the greater stability and a higher melting point. This transition may require several days. Cocoa butter must be slowly and evenly melted, preferably over a bath of warm water, to avoid formation of the unstable crystalline form and ensure retention in the liquid of the more stable beta crystals that will constitute nuclei upon which the congealing may occur during chilling of the liquid. Disadvantages of theobroma oil: 1. Polymorphism: when melt &solidify it form different crystal form depending on the temperature. if its melt at low temp, not exceed 36 °C it will form β-polymorph form which is stable form, if melted suddenly and quickly at high temperature then freezing or cooling it will form unstable γ form that melt at 15 °C. ‫اسوء وحده كاما‬ ‫احسن وحده بيتا‬ ‫الوسط الفا‬ 32  2. Adherence to the mold, this can be solved by using lubricant agent that is immiscible with the base. 3. Low m.p, this can be solved by added medication, adding white bees wax. 4. Low water absorbance (poor water-absorbing capacity), this can be solved by adding surface-active agent. 5. Stability problem (slow deterioration during storage, chemical instability). 6. Not suitable for warm countries. 7. Relatively high cost. Other fatty bases Other bases in this category include commercial products such as: Fattibase (triglycerides from palm, palm kernel, and coconut oils with self-emulsifying glyceryl monostearate and polyoxyl stearate), Wecobee bases (triglycerides derived from coconut oil) Witepsol bases (triglycerides of saturated fatty acids C12-C18 with varied portions of the corresponding partial glycerides). Water-Soluble and Water-Miscible Bases The main members of this group are glycerinated gelatin and polyethylene glycols. Glycerinated gelatin suppositories may be prepared by dissolving granular gelatin (20%) in glycerin (70%) and adding water or a solution or suspension of the medication (10%). A glycerinated gelatin base is most frequently used in preparation of vaginal suppositories, with which prolonged local action of the medicinal agent is usually desired. The glycerinated gelatin base is slower to soften and mix with the physiologic fluids than is cocoa butter and therefore provides a slower release. Glycerinated gelatin suppositories disadvantages A- Because glycerinated gelatin-based suppositories have a tendency to absorb moisture as a result of the hygroscopic nature of glycerin, they must be protected from atmospheric moisture to maintain their shape and consistency. B- Due to hygroscopic nature, they may have a dehydrating effect and irritate the tissues upon insertion. The water in the formula for the suppositories minimizes this action; however, if necessary, the suppositories may be moistened with water prior to insertion to reduce the initial tendency of the base to draw water from the mucous membranes and irritate the tissues. 33  Polyethylene glycols (PEG) Polyethylene glycols are polymers of ethylene oxide and water prepared to various chain lengths, molecular weights, and physical states, the most commonly used being polyethylene glycol 300, 400, 600, 1,000, 1,500, 1,540, 3,350, 4,000, 6,000, and 8,000. The numeric designations refer to the average molecular weight of each of the polymers. Various combinations of these polyethylene glycols may be combined by fusion, using two or more of the various types to achieve a suppository base of the desired consistency and characteristics. PEG PEG Melting range Melting range 300 - 15°C 3350 54°C -58°C 400 4°C -8°C 4600 57°C -61°C 600 20°C -25°C 6000 56°C -63°C 1000 37°C -40°C 8000 60°C -63°C 1450 43°C -46°C Polyethylene glycol suppositories PEG suppositories do not melt at body temperature but rather dissolve slowly in the body's fluids. Therefore, the base need not be formulated to melt at body temperature. It is possible to prepare suppositories from PEG mixtures having melting points considerably higher than body temperature. This property permits a slower release of the medication from the base once the suppository has been inserted, and permits convenient storage of these suppositories without need for refrigeration and without danger of their softening excessively in warm weather. Further, their solid nature permits slow insertion without fear that they will melt in the fingertips (as cocoa butter suppositories sometimes do). Because they do not melt at body temperature but mix with mucous secretions upon dissolution, PEG-based suppositories do not leak from the orifice, as many cocoa butter-based suppositories. PEG suppositories that do not contain at least 20% water should be dipped in water just before use to avoid irritation of the mucous membranes after insertion. This procedure prevents moisture being drawn from the tissues after insertion and the stinging sensation 34  Miscellaneous Bases The miscellaneous group of bases are mixtures of oleaginous and water- soluble or water-miscible materials. These materials may be chemical or physical mixtures. 1. Polyoxyl 40 stearate, a surface-active agent that is employed in a number of commercial suppository bases. Polyoxyl 40 stearate is a mixture of the monostearate and distearate esters of mixed polyoxyethylene diols and the free glycols, the average polymer length being equivalent to about 40 oxyethylene units. The substance is a white to light tan waxy solid that is water soluble. Its melting point is generally 39°C to 45°C. 2. Other surface-active agents useful in the preparation of suppository bases also fall into this broad grouping. Mixtures of many fatty bases (including cocoa butter) with emulsifying agents capable of forming water-in-oil emulsions have been prepared. These bases hold water or aqueous solutions. Preparation of suppositories Suppositories are prepared by three methods: (a) Molding from a melt (b) Compression (c) Hand rolling and shaping. The method most frequently employed both on a small scale and on an industrial scale is molding. Preparation by molding The steps in molding include: (a) Melting the base, (b) Incorporating any required medicaments, (c) Pouring the melt into molds, (d) Allowing the melt to cool and congeal into suppositories, (e) Removing the formed suppositories from the mold. Cocoa butter, glycerinated gelatin, polyethylene glycol, and most other bases are suitable for preparation by molding. Suppository Molds Molds in common use today are made from stainless steel, aluminum, brass, or plastic. The molds, which separate into sections, generally longitudinally, are opened for cleaning before and after preparation of a batch of 35  suppositories, closed when the melt is poured, and opened again to remove the cold molded suppositories. Care must be exercised in cleaning the molds, as any scratches on the molding surfaces will take away from the desired smoothness of the suppositories. Plastic molds are especially prone to scratching. Preparation by compression Suppositories may be prepared by forcing the mixed mass of the base and the medicaments into special molds using suppository-making machines. In preparation for compression into the molds, the base and the other formula ingredients are combined by thorough mixing, the friction of the process softening the base into a paste-like consistency. On a small scale, a mortar and pestle may be used. Heating the mortar in warm water (then drying it) greatly facilitates the softening of the base and the mixing. On a large scale, a similar process may be used, employing mechanical kneading mixers and a warm mixing vessel compression Preparation by hand rolling and shaping It is the oldest and simplest method of supp. preparation With ready availability of suppository molds of accommodating shapes and sizes, there is little requirement for today's pharmacist to shape suppositories by hand. Hand rolling and shaping is a historic part of the art of the pharmacist (it requires considerable practice and skill). Determination of the Amount of Base Required Generally, in preparing suppositories, the pharmacist calculates the amounts of materials needed for the preparation of one or two more suppositories than the number prescribed to compensate for the inevitable loss of some material and to ensure having enough material. In determining the amount of base to be incorporated with the medicaments, the pharmacist must be certain that the required amount of drug is provided in each suppository. 36  Because the volume of the mold is known (from the determined volume of the melted suppositories formed from the base), the volume of the drug substances subtracted from the total volume of the mold will give the volume of base required. Because the bases are solid at room temperature, the volume of base may be converted to weight from the density of the material. Medicated suppositories If the added amounts of medicaments are slight, they may be considered to be negligible, and no deduction from the total volume of base may be deemed necessary. In preparation of suppositories, it is generally assumed that if the quantity of active drug is less than 100 mg/ 2-g suppository weight then the volume occupied by the powder is insignificant and need not be considered Obviously, if a suppository mold of less than 2 g is used, the powder volume may need to be considered. However, if considerable quantities of other substances are to be used, the volumes of these materials are important and should be used to calculate the amount of base actually required to fill the mold. Example If 12 mL of cocoa butter is required to fill a suppository mold and if the medicaments in the formula have a collective volume of 2.8 mL, 9.2 mL of cocoa butter will be required. By multiplying 9.2 mL times the density of cocoa butter 0.86 g/ mL, it may be calculated that 7.9 g of cocoa butter will be required. After adjusting for the preparation of an extra suppository or two, the calculated amount is weighed. Density (Dose Replacement) Calculations for Suppositories The density factors of various bases and drugs need to be known to determine the proper weights of the ingredients to be used. Density factors relative to cocoa butter have been determined. If the density factor of a base is not known, it is simply calculated as the ratio of the blank weight of the base and cocoa butter The three methods of calculating the quantity of base that the active medication will occupy and the quantities of ingredients required are: (a) Dosage replacement factor (b) Density factor (c) Occupied volume method 37  Displacement value (D.V) Displacement value is defined as the quantity of drug that displaces one part of the base (eg. hydrocortisone has a displacement value of 1.5) Means 1.5g hydrocortisone displaces 1g the suppository base. If the density of the drug equals the density of the base. The drug will displace the same amount of base If the density of the drug is more than the density of the base the drug will displace low amount of base If the density of the drug is less than the density of the base the drug will displaces high amount of base DV. for liquids equals 1 Calculations using displacement values Prepare 8 codeine phosphate suppositories (D.V=1.1) using mold of 1g size each suppository containing 60mg of codeine phosphate Prepare 10 suppositories to compensate for any loss 60 X1 0 = 600mg = 0.6g of codeine phosphate Supp. Base 1g X 10 = 10g total weight of pure base Drug base 1.1 displace 1g base displaced = (1g X 0.6) / 1.1= 0.55 g 0.6 ? Amount of base needed is 10g - 0.55 = 9.45 g Example: Calculate the quantities required to make 8 theobroma oil supp. (2g mold) each containing 400 mg of zinc oxide (DV= 4.7). 1. Calculate the total weight of zinc oxide required. 0.4 X10 = 4g 2. Calculate what weight of base would be required to prepare 10 unmedicated supp. 2g X10 = 20 g 3. Determine what weight of base would be displaced by the medicament. Replaced base = wt. of drug/ D.V = 4 / 4.7= 0.85 4. Calculate, therefore, the weight of base required to prepare the medicated supps. 20 – 0.85 = 19.15 g wt. of base required Glycero-gelatin base has a density 1.2 times greater than theobroma oil. Therefore, a 1 g supp. mold will produce a 1 g theobroma oil supp., but a 1.2 g glycero-gelatin supp. This factor must be taken into account in displacement value calculations. 38 Example: Calculate the quantities required to make six glycero gelatin supp. (4 g mold), each containing100 mg aminophylline (Displacement value = 1.3) Drug 6 X 100 = 0.6 g Glycerin gelatin Base 6 X4g X1.2 = 28.8 g Glycerin gelatin Base replaced = 0.6 / 1.3 = 0.46 (by theobroma oil base) 0.46 X 1.2 = 0.55 g base displaced by the base (glycero gelatin) Base required 28.8 – 0.55 =28.25g of the base required Vaginal suppositories The most commonly used base for vaginal suppositories consists of combinations of the various molecular weight polyethylene glycols. To this base is frequently added surfactants and preservative agents, commonly the parabens. Many vaginal suppositories and other types of vaginal dosage forms are buffered to an acid pH usually about 4.5, consistent with the normal vagina. This acidity discourages pathogenic organisms and provides a favorable environment for eventual recolonization by the acid- producing bacilli normally found in the vagina. Rx Progesterone, micronized powder q.s. Polyethylene glycol 400 60% Polyethylene glycol 8000 40% Vaginal inserts Vaginal tablets are more widely used nowadays than are commercial vaginal supps; but compounded vaginal supps are very widely used. The tablets are easier to manufacture, more stable, and less messy. Vaginal tablets, frequently referred as vaginal inserts, are usually ovoid and are accompanied in their packaging with a plastic inserter, a device for easy placement of the tablet within the vagina. Vaginal tablets contain the same types of anti-infective and hormonal substances as vaginal supps. They are prepared by tablet compression and are commonly formulated to contain lactose as the base or filler, a disintegrating agent such as starch, a dispersing agent such as polyvinylpyrrolidone, and a tablet lubricant such as magnesium stearate. The tablets are intended to disintegrate within the vagina, releasing their medication. Some vaginal inserts are capsules of gelatin containing medication to be released intravaginally. 39 Packaging and storage Most commercial supps are individually wrapped in either foil or plastic. Some are packaged in a continuous strip, separated by tearing along perforations or otherwise separated in compartmented boxes to prevent contact and adhesion. Suppositories containing light-sensitive drugs are individually wrapped in an opaque material such as a metallic foil. Because supps. are adversely affected by heat, it is necessary to maintain them in a cool place. Cocoa butter supps. must be stored below 30°C and preferably in a refrigerator (2°C to 8°C). Glycerinated gelatin supps. can be stored at controlled room temperature (20°C to 25°C). Supps. made from a base of PEG may be stored at usual room temperatures. Supps. stored in high humidity may absorb moisture and tend to become spongy, whereas supps. stored in places of extreme dryness may lose moisture and become brittle. 40 Semi- solid dosage forms Chapter 10 Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems Eleventh Edition Objectives At the end of this topic, the student will be: Differentiate between the various types of semisolid bases on the basis of physical and chemical properties. List the criteria for the selection of a semisolid base to treat a topical affliction. Describe the methods to incorporate (an) active ingredient(s) into a semisolid base. Explain the difference between an ointment, a cream, and a gel. Compare and contrast an ophthalmic ointment base and a topical ointment base for application to the skin. 41  Semisolid Dosage Forms Ointments, creams, and gels are semisolid dosage forms intended for topical application. They may be applied to the skin , Placed on the surface of the eye , Or used nasally, vaginally and rectally. Most of these preparations are used for the effects of the therapeutic agents they contain. The unmedicated ones are used for their physical effects as protectants or lubricants. Topical preparations are used for both local and systemic effects. A topical drug (API) dosage form would be one that is designed to deliver the drug into the skin in treating skin disorders where the skin is the target organ. ‫( هو الشكل املصمم‬API) ‫إن شكل جرعة الدواء املوضعي‬ ‫لتوصيل الدواء إلى الجلد في عالج اضطرابات الجلد حيث‬ Systemic effects.‫يكون الجلد هو العضو املستهدف‬ Skin consists of three anatomical layers, the epidermis, the dermis and a subcutaneous fat layer. A transdermal product is designed to deliver drugs through the skin (percutaneous absorption) to the general circulation for systemic effects, with the skin not being the target organ. Systemic drug absorption should always be considered when using topical ‫هاي الفقره‬ ‫تخص‬ products if the patient is pregnant or musing, because drugs can enter the ‫الحوامل‬ fetal blood supply and breast milk and be transferred to the fetus or nursing infant. Recently there is an increase in the number of topical ointments, creams, and gels designed to deliver a drug systemically. This is often accomplished by addition of penetration enhancers to the topical vehicle The rate of drug movement across skin layer depends on: ‫حركة الدواء خالل طبقات الجسم‬ The drug concentration in the vehicle , Physicochemical properties of the drug substance such as solubility, partition coefficient, pKa, and molecular wight 42  The characteristics of the base or vehicle, hydrophilic– lipophilic character and viscosity Conditions of the skin itself “broken, hydrated other features of the skin. Ointments Ointments are semisolid preparations intended for external application to the skin or mucous membranes. Ointments may be medicated or Unmedicated. Unmedicated ointments are used for the physical effects they provide as protectants, emollients, or lubricants. Ointment bases, as described, may be used for their physical effects or as vehicles for medicated ointments. Ointment Bases Ointment bases are generally classified by the United States Pharmacopeia (USP) into four groups : 1. Oleaginous bases 2. Absorption bases 3. Water removable bases 4. Water soluble bases 43 Ideal properties of ointment bases 1. Stable 2. Neutral in reaction 3. Non-greasy 4. Not degreasing in action 5. Nonirritating 6. Non-dehydrating 7. Non-hygroscopic 8. Water-removable 9. Compatible with medications 10. Free from objectionable odor 11. Non-staining 12. Capable of serving as medium for drugs that are water and lipid soluble 13. Efficient on dry, oily or moist skin 14. Composed of readily available components of known chemical composition 15. Easily compounded by the pharmacist 16. Can melt or softened at body temperature 44  Mcq Oleaginous Bases ) Hydrocarbon bases) Oleaginous bases are also termed Hydrocarbon bases. On application to the skin 1. They have an emollient effect 2. Protect against the escape of moisture 3. They are effective as occlusive dressings 4. Can remain on the skin for long periods without drying out , Because of their immiscibility with water, are difficult to wash off. Water and aqueous preparations may be incorporated, but only in small amounts and with some difficulty. When powdered substances are to be incorporated into hydrocarbon bases, liquid petrolatum (mineral oil) may be used as the levigating agent Examples: ‫عندما يتم دمج املواد املسحوقة في القواعد‬ ‫ يمكن استخدام الفازلني‬،‫الهيدروكربونية‬ Petrolatum “Vaseline,” ‫السائل )الزيوت املعدنية( كعامل ترطيب‬ White petrolatum “White Vaseline” Yellow ointment White ointment. Petrolatum, USP, is a purified mixture of semisolid hydrocarbons obtained from petroleum. It has yellow to light amber color. it is also known as yellow petrolatum and petroleum jelly. A commercial product is Vaseline. White petrolatum, USP, is a purified mixture of semisolid hydrocarbons obtained from petroleum that has been wholly or nearly decolorized. White petrolatum is also known as white petroleum jelly. A commercial product is White Vaseline ‫منزوع اللون‬ 45  Yellow ointment, USP, this ointment has the following formula for the preparation of 1,000 g: Yellow wax 50 g Petrolatum 950 g Yellow wax is the purified wax obtained from the honey comb of the bee White Ointment, USP. This ointment differs from yellow ointment by substitution of white wax (bleached and purified yellow wax) and white petrolatum in the formula. White wax 50 g White Petrolatum 950 g 1. Absorption Bases These bases are of two types: a. Those that permit the incorporation of solutions resulting in the formation of w/o emulsion for example, Hydrophilic petrolatum. b. Those that are w/o emulsions that permit the incorporation of an additional quantities of aqueous solutions for example, lanolin They are used as emollients ‫مطريات‬ They are not easily removed from the skin by water washing, because the external phase is oleaginous ‫أنها ال توفر درجة االنسداد التي توفرها القواعد الزيتية‬ They do not provide the degree of occlusion afforded by the oleaginous bases Examples: Hydrophilic petrolatum, lanolin and modified lanolin. Hydrophilic Petrolatum, USP, has the following formula for the preparation of 1,000 g : Cholesterol 30 g Stearyl alc. 30 g White wax 80 g hydrophilic ‫مشتقات ال‬ White petrolatum 860 g petrolatum Commercial products, Aquaphor and Aquabase variations of hydrophilic petrolatum, have the capacity to absorb up to three times their weight in water ‫لها القدرة ع امتصاص‬ 46 ‫ثالث اضعاف وزنها من‬ ‫املاء‬  and are useful to help incorporate a water-soluble drug, for example, tobramycin sulfate, into an oleaginous ointment base Lanolin, USP Lanolin, USP (anhydrous lanolin), obtained from the wool of sheep, is a purified waxlike substance that has been cleaned, deodorized, and decolorized. It contains not more than 0.25% water. 2. Water-Removable Bases (Water-washable) They are oil-in- water emulsions (o/w) resembling creams. Because the external phase of the emulsion is aqueous, they are easily washed from skin and are often called water-washable bases. They may be diluted with water or aqueous solutions. They can absorb serous discharges. Hydrophilic Ointment, USP, is an example of this type of base. Hydrophilic Ointment, USP, has the following formula for 1,000 g: Methylparaben 0.25 g Propylparaben 0.15 g Sodium lauryl sulfate 10 g propylene glycol 120 g Stearyl alcohol. 250 g White petrolatum 250 g Purified water 370 g Water-Soluble Bases (Greaseless) ‫خاليه تماماً من الدهون‬ These bases do not contain oleaginous components. They are completely water washable. Because they soften greatly with the addition of water, large amounts of aqueous solutions are not effectively incorporated into these bases. Example: Polyethylene Glycol Ointment NF 47 The general formula for preparation of 1,000 g of PEG ointment is: PEG 335 400 g PEG 4000 600 g Classification and properties of USP ointment bases ‫العوامل حتى اختار قاعدة مثاليه‬ Selection of the appropriate ointment base Selection of the base to use in the formulation of an ointment depends on careful assessment of a number of factors, including the following : 1. The release rate of the drug substance from the base. 2. Desirability of topical or systemic action. 3. Desirability of occlusion of the moisture from the skin. 4. Stability of the drug in the ointment base. 5. Effect of drug on the consistency of the base. 6. Water wash ability of the base. 7. Characteristics of the surface to which it is applied. 48  For example, an ointment is generally applied to dry, scaly skin; a cream is applied to weeping or oozing surfaces Preparation of Ointments Depending primarily on the nature of the ingredients, ointments are prepared by two general methods. (a) Incorporation (b) Fusion ‫بهاي الطريقه نضع ماده ع اليمني‬ Incorporation Method ‫وماده ع اليسار ونخبط شويه شويه‬ In this method, the components are mixed until uniform preparation is attained. On small scale, the pharmacist may mix the components using mortar and pestle, or a spatula may be used to rub the ingredients together on an ointment slab (a large glass or porcelain plate or pill tile). If the components of an ointment react with metal (as does iodine), hard rubber or silicone spatulas may be used. The ointment is prepared by thoroughly rubbing and working the components together on the hard surface until the product is smooth and uniform. Incorporation of solids. When preparing an ointments by spatulation, the pharmacist works the ointment with a stainless steel spatula having a long, broad blade and periodically removes the accumulation of ointment on the large spatula with a smaller one. For incorporating a gummy material, such as camphor, pulverization by intervention can be used. The material is dissolved in a solvent and spread out on the pill tile. The solvent is allowed to evaporate, leaving a thin film of the material onto which the other ingredient or ingredients are spread. Incorporation of liquids. Liquid substances or solutions of drugs, are added to an ointment only after due consideration of an ointment base's capacity to accept the volume required. For example, only very small amounts of an aqueous solution may be incorporated into an oleaginous ointment, whereas hydrophilic ointment bases readily accept aqueous solutions. ‫ تضاف املواد السائلة أو محاليل األدوية إلى املرهم فقط‬.‫دمج السوائل‬ ‫ بعد‬49 ‫ على سبيل‬.‫األخذ في االعتبار قدرة قاعدة املرهم على قبول الحجم املطلوب‬ ‫ يمكن دمج كميات صغيرة جدًا فقط من املحلول املائي في مرهم‬،‫املثال‬ ‫ في حني تقبل قواعد املراهم املحبة للماء املحاليل املائية بسهولة‬،‫زيتي‬  Levigation in ointment preparation It often is desirable to reduce the particle size of a powder or crystalline material before incorporation into the ointment base so the final product will not be gritty. The reduction in particle size of the powder be done by levigating, or mixing the solid material in a vehicle in which it is insoluble to make a smooth dispersion. “wet grinding.” The levigating agent like mineral oil or glycerin should be physically and chemically compatible with the drug and the base. The levigating agent is used in an equal volume of the solid material. A mortar and pestle are used in levigation. Levigation allows both the reduction in particle size and the dispersion of the substance in the vehicle. Solids soluble in a common solvent that will affect neither the stability of the ‫ كون املاده‬drug nor the efficacy of the product may first be dissolved in that solvent (e.g., ‫املعدنية ماتاثر‬ ‫ ع استقرارية‬water or alcohol) and the solution added to the ointment base by spatulation ‫ املركب‬or in a mortar and pestle. On large scale, Ointment or roller mills can be used to force coarsely formed ointments through stainless steel or ceramic rollers to produce ointments uniform in composition and smooth in texture ،‫على نطاق واسع‬ ‫يمكن استخدام‬ ‫طواحني املراهم أو‬ ‫املطاحن األسطوانية‬ ‫لضغط املراهم ذات‬ ‫الشكل الخشن من‬ ‫خالل بكرات من‬ ‫الفوالذ املقاوم للصدأ‬ ‫أو السيراميك إلنتاج‬ ‫مراهم موحدة في‬ ‫التركيب وناعمة‬.‫امللمس‬ 50.‫ يتم دمج كل أو بعض مكونات املرهم وصهرها معًا وتبريدها مع التحريك املستمر حتى تتجمد‬،‫بهذه الطريقة‬ Fusion Method ً‫بهذة الطريقه نخلط املكونات كلها معا‬ By this method, all or some of the components of an ointment are combined and melted together and cooled with constant stirring until congealed. Other components like heat labile substances and volatile oils are added after cooling the mixture to prevent their decomposition and volatilization respectively. Substances may be added to the congealing mixture as Solutions Or insoluble powders levigated with a portion of the base. On a small scale, fusion may be done by using porcelain dish or glass beaker. On a large scale, it is carried out in large steam-jacketed kettles. After congealing, the ointment may be passed through an ointment mill “large scale”, or rubbed with a spatula or in a mortar “small scale” to ensure uniform texture. Medicated ointments containing components like beeswax, stearyl alcohol, high molecular wight PEGs are best prepared by fusion method rather than incorporation method. By fusion method, the materials with the highest melting points are heated to the lowest required temperature to produce a melt, then the additional substances are added with constant stirring during cooling the melt until the melt is congealed. In this way, not all components are subjected to the highest temperature. 51  Compendial requirements for ointments Ointments and other semisolid dosage forms must meet USP tests for : Microbial content Minimum fill Packaging, storage and labeling. Microbial Content With the exception of ophthalmic preparations, topical applications are not required to be sterile. Topical preparations must meet the acceptable standards for microbial contents Preparations that contain water tend to support microbial growth to a greater extent than water-free preparations. Dermatological products should be examined for the absence of Staphylococcus aureus and Pseudomonas aeruginosa. Other products intended for rectal, vaginal and urethral application should be tested for yeasts and molds. Preparations subjected to microbial growth must contain preservatives. ‫املواد‬ Among the antimicrobial preservatives used to inhibit microbial growth in ‫الحافظة‬ topical preparations are methylparaben, propylparaben, phenols, benzoic acid, sorbic acid, and quaternary ammonium salts. Microbial limit test is conducted for both raw materials and finished products. The USP states certain products should be routinely tested for microorganisms because of the way they are used. 52 Minimum fill The USP’s minimum fill test is used to determine the net weight or volume of the content of the filled containers to ensure proper content compared with the labeled amount. Packaging, Storage, and Labeling Ointments and other semisolid preparations are packaged either in large- mouth ointment jars or in metal or plastic tubes. Topical dermatologic products are packaged either in jars or in tubes, whereas ophthalmic, nasal, vaginal and rectal semisolid products are almost always packaged in tubes. Ointment jars are either clear or opaque glass or plastic. The jars and tubes should be compatible and stable with the intended product. ‫متوافقه‬ Tubes are superior to jars because they are lighter in weight, relatively inexpensive, conveniently used, compatible with most formulative ingredients, and provide greater protection against external contamination and environmental conditions. They are made of aluminum or plastic sometimes equipped with applicator. ‫تتفوق األنابيب على الجرار ألنها‬ ،‫ وغير مكلفة نسبيًا‬،‫أخف وزنًا‬ ‫ ومتوافقة مع‬،‫وسهلة االستخدام‬ ‫ وتوفر‬،‫معظم املكونات التركيبية‬ ‫حماية أكبر ضد التلوث الخارجي‬ ‫ وهي مصنوعة‬.‫والظروف البيئية‬ ‫من األلومنيوم أو البالستيك‬.‫ومجهزة أحيانًا بأداة تطبيق‬ Semisolid preparations must be stored in well-closed containers to protect against contamination and in a cool place to protect against product separation in heat. 53  When required, light-sensitive preparations are packaged in opaque or light- resistant containers. In addition to the usual labeling requirements for pharmaceutical products, the USP directs the labeling for certain ointments and creams include the type of base used (e.g., water soluble or water insoluble). Ophthalmic ointments Ophthalmic ointments differ from conventional ointments in that they must be sterile. In selecting an ointment base for an ophthalmic preparation, it must meet several qualities such as Must not be irritating to the eye Must permit the diffusion of the medicinal substance throughout the secretions bathing the eye ‫يجب ان ال تسد مدمع‬ ‫العني‬ Ointment bases used for ophthalmic should have a softening point