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Done By: Walaa Wahdan Advanced Technology Lecture #8 Last lecture we discussed the internal structure and arrangement that allow the solid solutions and dispersions affect the physiochemical properties of drugs, and change its dissolution and solubility. We may have different types of arrangements and configurations like: 1- Simple Eutectic mixtures: Are simple physical mixtures, for example: the eutectic mixture between the two local anesthetics procaine and lidocaine. We can form these mixtures by co-grinding or co-milling (grinding the crystals to bring them closer as much as possible). During the preparation of solid solutions and dispersions, using solvent method or melting method, rapid solidification of melt or evaporation of solvent may happen >>>> crystallization of component A and crystallization of component B both happening separately and individually resulting in crystal very close to each other. There is some sort of affinity between A&B >>> some sort of intermolecular inter action, bonds will form between A&B, which will weaken the bonds within same crystals in the molecules >>> as a result reduction in MP of both will happen (eutectic mixture: to melt together). - - - - Phase diagram : Not necessary that the presence of component A and B in eutectic mixture lead to reduction of the melting point below room temperature (as in lidocaine and procaine MIX). Melting point of the mixture will decrease depending on composition. E: common melting point of both. Examples of this type include phenacetin phenobarbital, chloramphenicol-urea, griseofulvin –succinic acid, paracetamol-urea, and the dispersions of griseofulvin and tolbutamide in polyethylene glycol (PEG-2000). Here the carrier not necessary always a high molecular weight polymer (PEG-2000), mostly it is a low molecular weight (like phenacetin –phenobarbital, succinic acid). Eutectic mixtures are systems with crystals of both A&B, what this mean? If we put a sample of this eutectic mixture in DSC (differential scanning calorimeter, a device for studying thermal phenomena). |Page1 Done By: Walaa Wahdan Advanced Technology Lecture #8 DSC: 2 electrical heaters (one for sample) with 2 aluminum bands, controlled by a computer processor. It contains sensors for measuring TEMP of the bands. We can control the amount of energy of both heaters. - - - Now we ask the computer to increase the temperature of both sample and reference bands at a rate of 10c/min (from 25c to 300c). The sample heater will give higher energy to increase the temperature of the sample from 25c to 35c after one minute (because it contains a mass), so the two bands will reach the same temperature after one minute. >>>> This will give as the following chart: Heat flow is the difference of energy between the two heaters. Heat flow > 0, will not stay as straight line; because of the thermal transitions of the sample (exothermic like degradation, breaking down the bonds and crystallization of a material or endothermic like melting, de-solvation and solid-solid transformation from one crystalline form to another or from crystalline form to amorphous form). In the melting process (endothermic), the amount of energy consumed for the elevation of temperature and for the melting of the sample. So the sample heater will give higher energy to maintain constant heating rate (heat flow will increase then decreases to the original state). In the eutectic mixture there are two peaks one for each crystals (A&B), MP will be on Temp. lower than the pure MP of the substances. 2- Solid solutions: Are homogenous molecular dispersion, (Component A&B dissolved in common solvent, sprayed by spray drier, which give droplet >>> losses solvent >>> 2 solutes concentrate and increasing concentration>> super saturation>> crystallization process). |Page2 Done By: Walaa Wahdan - - Advanced Technology Lecture #8 If A&B have high affinity for each other, then it may form co-crystals (true molecular solution). If solidification happens, then all the crystals will be the same as this. Each sample will contain the same composition (but in the eutectic mixture previously, not necessary each sample contains the composition, because it’s a physical mixture of crystal). If we pass the solid solution in DSC, it will give one peak because we have single solid phase. The ratio of 2 components in the crystal depends on: ratio of drug and carrier, affinity of both and most stable arrangement between them (but mostly the carrier exist in higher ratio to form the water soluble matrix which will increase the dissolution). Drug called co-former (lower ratio). There are two types of arrangement of solid solutions (for co-former and carrier or guest and host molecules): - These arrangements depend on: 1. Molecular size of drug compared to carrier. 2. Affinity of drug to the carrier (ability to form intermolecular interactions). 1. Substitutional ()احالل: both must have the same size and can make intermolecular interactions to contribute to the formation of the crystals (similarity in the intermolecular interactions of both). Ex: lactose, saccharin sodium 2. Interstitial: carrier and co-former have different size (molecular size of drug lower than size of carrier – most important requirement-) and mostly without intermolecular interactions (in case of polymer –PVP- as a carrier or highly hydrophobic drug with hydrophilic polymer); guest molecules will fill the voids between host molecules. *more common* 3- Glass solutions and suspensions: Amorphous (not crystalline solids). - - Here the droplets dryed gradually, the polymer concentration increases and the solution become more viscuos >>> molecules with lower ability to diffuse toward each other to form supra molecular structure (crystals)>>> lower molecular mobility to form the most stable arrangment. Particles with amorphous carrier and drug as molecules formed (glass solution, amorphous solid). Glass: amorphous solid below glass transtion temperature. Glass transition temperature: is the temperature above which an amorphous material exist in ruppary state and below which it exist in glassy state. |Page3 Done By: Walaa Wahdan - 4- Advanced Technology Lecture #8 Glass suspension: means some molecules could meet to form supramolecular structure (amorphous particles) dispersed within the amorphous carrier. Amorphous Precipitations in a Crystalline Carrier: The solidification of the amorphous drug particles in crystalline carrier, depending on the proparties of the drug, carrier and the procees. 5- Complex formation: The interactions between the drug and carrier lead to complex formation (new chemical entity). With reversal property to give the free drug , it can lead to good or poor properties. Ex: hydroxy propyl beta cyclodextrane, digoxin and hydroquinone, ibuprofen and caffeine Good luck |Page4