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Part 1 Liquid Crystals Surfactant + water >>>> different phases. Phase type determined by: • Surfactant concentration (illustrating figures) • Temperature (GMO binary phase diagrams) • Additives (ternary phase diagrams) Liquid crystals are substaces that exhibit a phase of matter that has properties between those of a conventional liquid, and those of a solid crystal. Hence LC show anisotropy. Liquid crystals are either lyotropic or thermotropic. Figure The ‘‘ideal’’ sequence of phases as a function of amphiphile concentration. Names and abbreviations for the different mesophases are: micelles (L1), micellar cubic (I1), hexagonal (H1), bicontinuous cubic (v1), lamellar (La), reversed bicontinuous cubic (v2), reversed hexagonal (H2), reversed micellar cubic (I2), and reversed micelles (L2), where subscripts 1 and 2 refer to ‘‘normal’’ and ‘‘reversed’’ phases, respectively. Lamellar phases can be found in different phase states, including: lamellar crystalline (Lc), lamellar gel (Lb), and lamellar fluid (La). Ref. Phys. Chem. Chem. Phys., 2006, 8, 4957–4975 | 4957 Figure: In a system of water, ionic surfactant, and long-chain alcohol three phases are important cosmetically. The aqueou solution (lower left) contains spherical micelies, the lameliar liquid crystal is located in the middle, and the alcohol solution (top) contains inverse micelles. J. Soc. Cosmet. Chem., 41, 155-171 (May/June 1990) Pictures of different systems made by a polarized microscope. Micellar and reverse micellar have no optical activity. Ref. Langmuir, Vol. 20, No. 5, 2004 1643 Part 2 Liquid Crystal in Cosmetics emulsions Introduction: Lipids in the SC are organized in a bilayer LC-like structure. Skin dryness is prevented by keeping liquid like nature of the bilayers. Moisturising agents are required to improve skin hydration and increase water retention. Lamellar LCs are good candidate. What are the components of the LC base? a Fatty surfactant: GMO, long chain alcohols,.. (too lipophilic to stabilize o/w emulsion alone) b high HLB surfactant. What is the phases produced when dispersing a or b in water separately and combined ? a too hydrophobic to form swollen lamellar phase b forms only micelles a and b >gel structure (b penetrates the layers of a and permits swelling and lamellar liquid crystal formation) Heating followed by cooling >> lamellar crystalline gel network Figure: In a system of water, ionic surfactant, and long-chain alcohol three phases are important cosmetically. The aqueou solution (lower left) contains spherical micelies, the lameliar liquid crystal is located in the middle, and the alcohol solution (top) contains inverse micelles. J. Soc. Cosmet. Chem., 41, 155-171 (May/June 1990) How does the lamellar LC phases form? At optimum blend of a and b. Suggested structure for the lamellar LC (at T>Tk) Suggested structure for the lamellar gel phase (at T<Tk) Advantages of the LC phases: • emulsion definition: “An emulsion is a mixture of two liquids, one of which is dispersed in the other in the form of liquid droplets and/or as liquid crystals” • emulsion stability, • Prolong hydration properties, • Controlled drug delivery, • Easy to formulate, • Well-liked skin feel. Part 3 Formulation of an oral dosage form utilizing the properties of cubic liquid crystalline phases of glyceryl monooleate Ref.: European Journal of Pharmaceutics and Biopharmaceutics 53 (2002) 343– 352 Introduction: GMO: FDA -approved food additive, The unique properties of cubic liquid crystalline phases formed from GMO systems have been utilized for the preparation of controlled release systems and in topical and mucosal drug delivery systems due to their adhesive properties. Investigated model drug: Furosemide (diuretic). Disadvantage of conventional dosage forms: low bioavailability and short period of peak diuresis. Suggested solutions: Sustained release formulations (showed reduced bioavailability of the drug in comparison with immediate release dosage forms), Modified release dosage form having a longer gastric residence time (a correlation was made between gastrointestinal transit and furosemide). Aim: Investigation of the cubic liquid crystalline phases of GMO to formulate an oral drug delivery system for furosemide. Furosemide when dispersed in GMO and filled into hard gelatin capsules is expected, when exposed to gastrointestinal fluids at body temperature, to swell forming the cubic liquid crystalline phase. The system is expected: To produce sustained release, To be retained in the stomach through its bioadhesive nature. Glyceryl Monooleate Also known as monoolein or GMO Polar lipid, insoluble but swallable in water, Semisolid, melting point 35-37 deg. Methods 1. Preparation of different GMO mixtures a. Preparation of GMO-drug mixtures: GMO > melt (at 45deg in water bath)> add furosemide, PEG 400 and trisodium phosphate (TSP)> continuous mixing > complete dispersion. Store at 5 C in a dark place. b. Samples for phase diagram construction: GMO in glass vials>melt> add warm aqueous media (water, or simulated intestinal fluids without enzymes (SIF) or simulated gastric fluids without enzymes (SGF)) >mix. c. Samples for additives effect on the cubic phase formation: GMO in glass vials>melt> add additives > add warm distilled sufficient to form the cubic phase. Store the well closed samples (b, c) at 37 C in a dark place for 12 h in order to reach equilibrium conditions before testing. Identification of GMO phases Observation of viscosities and optical properties changes upon heating at constant rate (4 C/ min) on a hot stage connected to polarizing microscope. Results: Reversed micellar phase (L2): clear liquid and isotropic. Cubic phase: very viscous gel and isotropic Other phases were less viscous than the cubic liquid crystalline phase and look radiant when viewed between crossed polarizers. Lamellar phase (La) had a pattern of ‘oily streaks’ and Maltese crosses; Reversed hexagonal phase: fan-like textures. The results proved that the cubic phase of GMO would exist at body temperature in the presence of gastrointestinal fluid. Fig. 1. Phase diagrams of (a) GMO/distilled water system, (b) GMO/SIF system, (c) GMO/SGF system. SIF, simulated intestinal fluid; SGF, simulated gastric fluid; L2, reversed micellar phase; La, lamellar phase; C, cubic phase; HII, reversed hexagonal phase. Fig. 2. Phase diagram of GMO containing 5% furosemide in water. Observation of the melting behavior of GMO: furosemide and their mixtures using a hot-stage microscope at 4 C/min heating rate. Thermal analysis: DSC thermograms of GMO, furosemide each alone and in mixtures were recorded at heating rate of 10 C/min. For mixtures containing furosemide and GMO, the endothermic event attributed to the melting o GMO was not affected by the presence of furosemide. Partitioning of furosemide between aqueous test solutions and GMO in the cubic liquid crystalline form: • known concentration of furosemide + test solution placed in a 100-ml stoppered conical flask in a shaker water bath maintained at 37.0 deg., protected from light to avoid photodegradation of Furosemide, • Add One gram of GMO to each flask with continuous shaking, • At selected time interval, withdraw 5-ml aliquots, were filter, through a 0.45-mm membrane filter and measure furosemide concentration (spectrophotometrically). • Runs were done in triplicate. The apparent lipid bilayer/water partition coefficient of furosemide versus the corresponding pH value (at 37 C). Dissolution tests: Samples accurately weighed containing the equivalent of 40 mg furosemide were filled into hard gelatin transparent capsule size (0) and used for dissolution testing within 24 h of preparation. Dissolution tests were carried out in triplicates using USP apparatus II (paddle) (protected from light). Release rates of furosemide from GMO containing different drug loadings in comparison with an immediate release furosemide capsule using SGF at 37 C Effect of changing the pH of the dissolution medium on the release rate of furosemide from formula containing furosemide/TSP/PEG 400/ GMO (5:5:10:80) using apparatus I; 100 rpm. Conclusion ……… A formula containing furosemide/TSP/PEG 400/GMO in the ratio 5:5:10:80, respectively, was found to have optimum properties concerning release characteristics and mucoadhesion. However, future work needs to b concentrated on the evaluation of in vivo mucoadhesive studies on the selected formulation. Polarized Microscope Q.1 What does it mean for the light to be “Polarized” ? Natural sunlight and almost every other form of artificial illumination transmits light waves whose electric field vectors vibrate in all perpendicular planes with respect to the direction of propagation. A light wave that is vibrating in more than one plane is referred to as unpolarized light. If the electric field vectors are restricted to a single plane by filtration of the beam with specialized materials, then the light is referred to as plane or linearly polarized with respect to the direction of propagation, and all waves vibrating in a single plane are termed plane parallel or plane-polarized. Q.2 What is meant by Plane and crossed polarized light? In the figure, the incident light electric field vectors are vibrating perpendicular to the direction of propagation in an equal distribution of all planes before encountering the first polarizer. Polarizer 1 is oriented vertically to the incident beam so it will pass only the waves that are vertical in the incident beam. The wave passing through polarizer 1 is subsequently blocked by polarizer 2 because the second polarizer is oriented horizontally with respect to the electric field vector in the light wave. The concept of using two polarizers oriented at right angles with respect to each other is commonly termed crossed polarization and is fundamental to the practice of polarized light microscopy. Image contrast arises from the interaction of plane-polarized light with a birefringent specimen to produce two individual wave components that are each polarized in mutually perpendicular planes. The velocities of these components are different and vary with the propagation direction through the specimen. When an anisotropic specimen is brought into focus and rotated through 360 degrees on a circular polarized light microscope stage, it will sequentially appear bright and dark. Optical Activity Many molecules have an interesting property in that they can rotate polarized light. Some drugs molecules can rotate or change the direction the light vibrates, so if we place a container of the drug solution in the light path, between the two filters (polarizers) in the figure , then in order to look “light,” or “dark”, the second filter will have to be rotated differently to make up for how much the drug molecule rotates the light. Drugs can be identified by which direction and how much it rotates the light. For example, glucose rotates polarized light to the right so it’s also known as dextrose. Fructose rotates polarized light to the left, so it’s also known as levulose. Origins of optical activity. An electronic transition is the result of the movement of charges when a molecule is exposed to light. The electronic transition has an associated magnetic transition that is perpendicular to it. The energy of a transition depends on the electric dipole moment and the magnetic dipole moment induced by the action of light on the electrons in the molecule. The rotational strength of a transition is the imaginary part of the dot product of the electric dipole induced by the light and the magnetic dipole induced by the light. If a molecule has a plane or center of symmetry either the sum of all the induced electric and magnetic dipoles is zero, or the vectors representing the magnetic and electric dipoles are perpendicular to one another. The result is that there is no optical activity since the cosine of 90 deg. equals 0. There are several cases showing asymmetry in the molecule and in these cases the molecule is optically active. The End