PERIODATE OXIDATION OF DIOL AND OTHER FUNCTIONAL GROUPS: ANALYTICAL AND STRUCTURAL APPLICATIONS

By ROBERT WILLIAMS

TABLE OF CONTENTS AEROSOL ASSISTED FAST FORMULATING UNIFORM PHARMACEUTICAL POLYMER MICROPARTICLES WITH VARIABLE PROPERTIES TOWARD PH SENSITIVE CONTROLLED DRUG RELEASE 1 CO ASSEMBLY OF GRAPHENE OXIDE AND ALBUMIN PHOTOSENSITIZER NANOHYBRIDS TOWARDS ENHANCED PHOTODYNAMIC THERAPY 16 THE CONSTRUCTION OF AN AQUEOUS TWO PHASE SYSTEM TO SOLVE WEAK AGGREGATION OF GIGAPOROUS POLY STYRENE DIVINYL BENZENE MICROSPHERES 27 EFFECT OF SMALL REACTION LOCUS IN FREE RADICAL POLYMERIZATION CONVENTIONAL AND REVERSIBLE DEACTIVATION RADICAL POLYMERIZATION 39 GIGAPOROUS POLYMERIC MICROSPHERES 53 GREEN SYNTHESIS OF SMART METAL POLYMER NANOCOMPOSITE PARTICLES AND THEIR TUNEABLE CATALYTIC ACTIVITIES 63 AMPHIPHILIC FLUORINATED BLOCK COPOLYMER SYNTHESIZED BY RAFT POLYMERIZATION FOR GRAPHENE DISPERSIONS 77 89 FABRICATION OF ALKOXYAMINE FUNCTIONALIZED MAGNETIC CORE SHELL MICROSPHERES VIA REFLUX PRECIPITATION POLYMERIZATION FOR GLYCOPEPTIDE ENRICHMENT 104 POLYDOPAMINE PARTICLE AS A PARTICULATE EMULSIFIER 118 IMPROVED STABILITY OF EMULSIONS IN PREPARATION OF UNIFORM SMALL SIZED KONJAC GLUCOMANNA KG M MICROSPHERES WITH EPOXY BASED POLYMER MEMBRANE BY PREMIX MEMBRANE EMULSIFICATION 133 INITIATOR SYSTEMS EFFECT ON PARTICLE COAGULATION AND PARTICLE SIZE DISTRIBUTION IN ONE STEP EMULSI ON POLYMERIZATION OF STYRENE 146 POLY N ISOPROPYLACRYLAMIDE POLY ACRYLIC ACID WITH SEMI IPN STRUCTURE BY ONE STEP METHOD AEROSOL ASSISTED FAST FORMULATING UNIFORM PHARMACEUTICAL POLYMER MICROPARTICLES WITH VARIABLE PROPERTIES TOWARD PH SENSITIVE CONTROLLED DRUG RELEASE ABSTRACT MICROENCAPSULATION IS HIGHLY ATTRACTIVE FOR ORAL DRUG DELIVERY MICROPARTICLES ARE A COMMON FORM OF DRUG CARRIER FOR THIS PURPOSE THERE IS STILL A HIGH DEMAND ON EF CIENT METHODS TO FABRICATE MICROPARTICLES WITH UNIFORM SIZES AND WELL CONTROLLED PARTICLE PROPERTIES IN THIS PAPER UNIFORM HYDROXYPROPYL METHYLCELLULOSE PHTHALATE HPMCP BASED PHARMACEUTICAL MICROPARTICLES LOADED WITH EITHER HYDROPHOBIC OR HYDROPHILIC MODEL DRUGS HAVE BEEN DIRECTLY FORMULATED BY USING A UNIQUE AEROSOL TECHNIQUE I E THE MICRO UIDIC SPRAY DRYING TECHNOLOGY A SERIES OF MICROPARTICLES OF CONTROLLABLE PARTICLE SIZES SHAPES AND STRUCTURES ARE FABRICATED BY TUNING THE SOLVENT COMPOSITION AND DRYING TEMPERATURE IT IS FOUND THAT A MORE VOLATILE SOLVENT AND A HIGHER DRYING TEMPERATURE CAN RESULT IN FAST EVAPORATION RATES TO FORM MICROPARTICLES OF LARGER LATERAL SIZE MORE IRREGULAR SHAPE AND DENSER MATRIX THE NATURE OF THE MODEL DRUGS ALSO PLAYS AN IMPORTANT ROLE IN DETERMINING PARTICLE PROPERTIES THE DRUG RELEASE BEHAVIORS OF THE PHARMACEUTICAL MICROPARTICLES ARE DEPENDENT ON THEIR STRUCTURAL PROPERTIES AND THE NATURE OF A SPECI C DRUG AS WELL AS SENSITIVE TO THE PH VALUE OF THE RELEASE MEDIUM MOST IMPORTANTLY DRUGS IN THE MICROPARTICLES OBTAINED BY USING A MORE VOLATILE SOLVENT OR A HIGHER DRYING TEMPERATURE CAN BE WELL PROTECTED FROM DEGRADATION IN HARSH SIMULATED GASTRIC UIDS DUE TO THE DENSE STRUCTURES OF THE MICROPARTICLES WHILE THEY CAN BE FAST RELEASED IN SIMULATED INTESTINAL UIDS THROUGH PARTICLE DISSOLUTION THESE PHARMACEUTICAL MICROPARTICLES ARE POTENTIALLY USEFUL FOR SITE SPECI C ENTERIC DELIVERY OF ORALLY ADMINISTERED DRUGS KEYWORDS AEROSOL METHOD SPRAY DRYING POLYMER MICROPARTICLE MICROENCAPSULATION DRUG DELIVERY 1 INTRODUCTION MICROENCAPSULATION IS HIGHLY IMPORTANT FOR ORAL AND TRANSDERMAL DRUG DELIVERIES 1 5 IN PARTICULAR MICROPARTICLES AS DRUG CARRIERS CAPABLE OF PH SENSITIVE CONTROLLED RELEASE PLAY A VITAL ROLE IN SITE SELECTIVE SUCH AS ENTERIC DELIVERY OF ORALLY ADMINISTERED DRUGS FOR THERAPEUTIC APPLICATIONS 6 11 IDEALLY THE EMBEDDED DRUGS SHOULD BE WELL PROTECTED BY THE CARRIER MATERIALS FROM DEGRADATION IN THE HIGHLY ACIDIC GASTRIC UID AND RELEASED IN A DESIRABLE WAY WHILE REACHING THE INTESTINAL TRACT FOR EF CIENT ABSORPTION 12 13 THEREFORE THE SELECTION AND CONTROL OF THE STRUCTURAL PROPERTIES OF MICROPARTICLE CARRIERS ARE VERY IMPORTANT 14 15 HYDROXYPROPYL METHYLCELLULOSE PHTHALATE HPMCP A GENERALLY RECOGNIZED AS SAFE GRAS CELLULOSE DERIVATIVE IS WIDELY ADOPTED AS AN ENTERIC POLYMER FOR DRUG DELIVERY DUE TO ITS PH DEPENDENT SOLUBILITY I E LOW SOLUBILITY IN THE HARSH GASTRIC UID WHILE THE OPPOSITE IN THE INTESTINAL TRACT 12 16 17 HOWEVER LOW SOLUBILITY DOES NOT 1 NECESSARILY GUARANTEE DRUG PROTECTION THE STRUCTURAL PROPERTIES ESPECIALLY THE PARTICLE SIZE UNIFORMITY AND SURFACE INTERNAL POROSITY SHOULD ALSO BE WELL CONTROLLED TO MAKE THE ENCAPSULATED DRUGS WELL PROTECTED AND TO UNDERSTAND RELEASE BEHAVIORS 2 3 18 19 ADDITIONALLY DRUG CARRIER INTERACTIONS SHOULD BE CONSIDERED FOR BETTER DRUG PROTECTION AND CONTROL OF PARTICLE PROPERTIES 2 TO FABRICATE MICROPARTICLES FOR THE PURPOSE OF CONTROLLED DRUG DELIVERY A SERIES OF APPROACHES HAVE BEEN DEVELOPED SUCH AS THE EMULSION METHOD 10 20 22 MICRO UIDICS 20 23 ELECTROSTATIC DROPLET METHOD 24 25 MEMBRANE LTRATION 26 SUPERCRITICAL CO2 PROCESSING 27 28 TEMPLATING 29 ELECTROHYDRODYNAMIC ATOMIZATION TECHNIQUE 30 AND SO ON COMPARATIVELY AEROSOL BASED TECHNIQUES PARTICULARLY SPRAY DRYING TECHNOLOGY IS A CONTINUOUS AND LOW COST METHOD TO MANUFACTURE POWDERED MICROPARTICLES 31 33 IN ADDITION MICROPARTICLES PREPARED THROUGH AEROSOL METHODS ARE USUALLY OF HIGH CHEMICAL UTILIZATION EF CIENCY THEORETICALLY 100 THROUGH AVOIDING WASHING AND PURI CATION STEPS IN AEROSOL METHODS LIQUIDS ARE ATOMIZED TO DROPLETS WHICH ARE SUBSEQUENTLY DRIED AND OR THERMALLY TREATED TO OBTAIN TARGETED PARTICLES 34 37 DURING FAST SOLVENT EVAPORATION SOLUTES IN LIQUID DROPLETS ARE DRIVEN AWAY FAR FROM EQUILIBRIUM AND FORCED TO BE ASSEMBLED TOGETHER LEADING TO UNIQUE CO ASSEMBLY MECHANISMS AND BOUNDARY PHENOMENA AND THEN TO NOVEL MATERIALS WITH UNIQUE STRUCTURES SUCH AS MESOPOROUS CORE SHELL AND HIERARCHICAL STRUCTURES 34 41 CONVENTIONAL AEROSOL TECHNIQUES SUCH AS CONVENTIONAL SPRAY DRYING HOWEVER OFTEN PRODUCE MICROPARTICLES WITH RELATIVELY SMALL SIZES TYPICALLY TENS OF NANOMETERS TO A FEW MICROMETERS AND VERY BROAD PARTICLE SIZE DISTRIBUTIONS 34 42 MAINLY DUE TO THE ATOMIZED DROPLETS OF A WIDE RANGE OF SIZE DISTRIBUTIONS AND COMPLEX TRAVELLING TRAJECTORIES WHICH EXPERIENCE DIFFERENT DRYING HISTORIES WITHIN THE SAME PRODUCT BATCH CONSEQUENTLY THE EFFECT OF A PARTICULAR PROCESS PARAMETER ON MICROPARTICLE PROPERTIES AND A PARTICULAR PROPERTY ON PARTICLE PERFORMANCE CANNOT BE ACCURATELY GURED OUT TO TACKLE SUCH DRAWBACKS WE HAVE RECENTLY INTRODUCED A SPECIALLY DESIGNED MICRO UIDIC JET SPRAY DRYER MFJSD THAT IS CAPABLE OF PRODUCING UNIFORM AND LARGE SIZED MICROPARTICLES RANGING FROM 5 TO 300 M WITH CONTROLLABLE CHARACTERISTICS AND FUNCTIONALITIES 43 45 THE PROPERTIES OF SPRAY DRIED MICROPARTICLES ARE SIGNI CANTLY IN UENCED BY PRECURSOR FORMULATION SUCH AS COMPOSITION AND SOLVENT TYPE AND SPRAY DRYING CONDITIONS SUCH AS AIR OW RATE AND DRYING TEMPERATURE THEREFORE IN ORDER TO PRODUCE PHARMACEUTICAL MICROPARTICLES CAPABLE OF PH SENSITIVE DRUG RELEASE THE STRUCTURES OF THE MICROPARTICLES SHOULD BE PRECISELY CONTROLLED AND THE CORRELATIONS BETWEEN PARTICLE STRUCTURE AND DRUG RELEASE BEHAVIOR SHOULD BE UNDERSTOOD HEREIN IN THIS WORK FOR THE RST TIME WE EXPLORED THE USE OF MFJSD FOR THE ONE STEP STRAIGHTFORWARD FABRICATION AND CONTROL OF STRUCTURAL PROPERTIES OF DRUG LOADED HPMCP BASED MICROPARTICLES FOR PH SENSITIVE DRUG DELIVERY HYDROCORTISONE AND LYSINE WERE SELECTED AS A HYDROPHOBIC AND A HYDROPHILIC MODEL DRUG RESPECTIVELY TO INVESTIGATE THEIR IN UENCES ON PARTICLE PROPERTIES AND RELEASE BEHAVIORS THE EFFECTS OF PRECURSOR FORMULATION INCLUDING SOLVENT COMPOSITION AND DRYING TEMPERATURE ON SPRAY DRIED PARTICLE CHARACTERISTICS AND RELEASE BEHAVIORS HAVE BEEN STUDIED IN DETAIL A SERIES OF UNIFORM HPMCP BASED PHARMACEUTICAL MICROPARTICLES CAPABLE OF PH SENSITIVE DRUG DELIVERY HAVE BEEN SUCCESSFULLY FABRICATED AND THEIR DRUG RELEASE BEHAVIORS HAVE BEEN WELL CORRELATED WITH THEIR STRUCTURAL PROPERTIES 2 MATERIALS AND METHODS 2 1 CHEMICALS HYDROXYPROPYL METHYLCELLULOSE PHTHALATE HPMCP WAS PURCHASED FROM YOLNE SHANGHAI CHINA HYDROCORTISONE OF BIOCHEMICAL REAGENT WAS PURCHASED FROM SINOPHARM CHEMICAL REAGENT CO LTD SHANGHAI CHINA LYSINE WAS KINDLY PROVIDED BY COFCO BEIJING CHINA ETHANOL ACETONE HYDROCHLORIC ACID AMMONIUM HYDROXIDE SOLUTION 25 28 WT DIMETHYL SULFOXIDE NINHYDRIN AND LITHIUM HYDROXIDE MONOHYDRATE WERE OF ANALYTICAL GRADE DEIONIZED WATER MILLI Q WAS USED THROUGHOUT THE EXPERIMENTS WHEREVER REQUIRED PERIODATE OXIDATION OF DIOL AND OTHER FUNCTIONAL GROUPS 2 2 2 PRECURSOR PREPARATION THE PRECURSORS FOR SPRAY DRYING WERE PREPARED BY DIRECTLY DISPERSING HPMCP INTO CERTAIN SOLVENTS TO INVESTIGATE THE EFFECTS OF SOLVENTS DIFFERENT FORMULATIONS OF PRECURSORS WERE PREPARED TABLE S1 THE TOTAL MASS CONTENT OF EXCIPIENTS WAS SET TO BE 2 5 W V A CERTAIN AMOUNT TYPICALLY 2 5 WT OF A SPECI C MODEL DRUG WAS ADDED INTO THE PRECURSOR SOLUTIONS FOR ONE STEP FORMULATING PHARMACEUTICAL MICROPARTICLES 2 3 MICROPARTICLE FABRICATION BRIE Y THE PRECURSOR SOLUTIONS WERE FED INTO A STANDARD STEEL RESERVOIR AND COMPRESSED AIR WAS USED TO FORCE THE LIQUID IN THE RESERVOIR TO JET THROUGH THE MICRO UIDIC AEROSOL NOZZLE MFAN HOME MADE SUZHOU CHINA FIGURE S1A THE LIQUID OWING RATE WAS CONTROLLED BY CHANGING THE AIR PRESSURE THE LIQUID JET WAS BROKEN UP INTO DROPLETS BY DISTURBANCE FROM VIBRATING PIEZOCERAMICS ON THE NOZZLE THE VIBRATION FREQUENCY WAS TUNED IN ORDER TO OBTAIN MONODISPERSE DROPLETS A NEW GENERATION OF MFJSD 6 HOME MADE SUZHOU CHINA FIGURE S1B WAS USED TO PRODUCE MICROPARTICLES THE INLET TEMPERATURE WAS CONTROLLED FROM 95 TO 205 C FOR VARIOUS PRECURSOR SOLUTIONS THE OW RATE OF THE HOT AIR WAS 250 L MIN THE COLLECTED MICROPARTICLES WERE STORED IN DESICCATORS FOR FURTHER CHARACTERIZATIONS AND DRUG RELEASE TESTS 2 4 PARTICLE CHARACTERIZATION THE MORPHOLOGY AND STRUCTURE OF MICROPARTICLES BEFORE AND AFTER DRUG RELEASE TESTS WERE EXAMINED BY SCANNING ELECTRON MICROSCOPY SEM S 4700 HITACHI HIGH TECHNOLOGIES CORPORATION TOKYO JAPAN PARTICLE SIZE AND SIZE DISTRIBUTION WERE ACQUIRED BY ANALYZING SEM IMAGES CONTAINING OVER 1000 PARTICLES BY USING SHINESO SHINESO HANGZHOU CHINA THE AVERAGE PARTICLE SIZE D WAS DE NED AS D N I 1 DI N AND THE SPAN OF SIZE DISTRIBUTION WAS DESCRIBED AS SPAN D90 D10 D50 WHERE DI WAS THE DIAMETER OF THE I TH PARTICLE N WAS THE TOTAL NUMBER OF MICROPATICLES AND D90 D50 AND D10 WERE THE CUMULATIVE PARTICLE SIZES AT 90 50 AND 10 RESPECTIVELY MICROPARTICLE DENSITY WAS ASSESSED BY LLING 0 5 2 G POWDERS INTO A 5 ML GRADUATED CYLINDER AND THE WEIGHT AND VOLUME OCCUPIED BY THE POWDER WERE RECORDED THE MASS VOLUME RATIO BEFORE TAPPING WAS CALCULATED AS BULK DENSITY THE TAP DENSITY OF THE POWDER WAS THEN EVALUATED BY TAPPING THE SYRINGE ONTO A LEVEL SURFACE AT A HEIGHT OF ABOUT 2 CM UNTIL NO CHANGE IN VOLUME IS OBSERVED 46 CARR S INDEX WAS CALCULATED AS TAP DENSITY BULK DENSITY 100 TAP DENSITY THE CRYSTALLINE CHARACTERISTICS OF THE RAW DRUGS AND MICROPARTICLES WERE TESTED BY USING THE POWDER X RAY DIFFRACTION XRD TECHNIQUE X PERT PRO MPD PANALYTICAL B V ALMELO NETHERLANDS WITH A CU K RADIATION SOURCE AND A SCAN RANGE OF 1 MIN THE POWDERS WERE PRESSED ONTO QUARTZ BLOCKS BY USING A GLASS SLIDE FOR DIRECT DATA RECORDING 2 5 IN VITRO DRUG RELEASE TEST THE SWELLING AND DISSOLUTION BEHAVIORS OF TYPICAL PHARMACEUTICAL MICROPARTICLES WERE STUDIED BRIE Y A SMALL AMOUNT OF MICROPARTICLES WAS PLACED ON A GLASS SLIDE AND A DROP OF PBS PHOSPHATE BUFFER SOLUTION OR SIMULATED GASTRIC JUICE 0 1 M HCL AT AROUND 25 C WAS DROPPED ON THE GLASS SURFACE NEXT TO THE MICROPARTICLES THEN THE MICROPARTICLES CONTACTED WITH WATER AND WERE IN LTRATED SLOWLY THE DISSOLUTION PROCESSES IN PBS AND SWELLING PHENOMENA IN SIMULATED GASTRIC JUICE WERE RECORDED USING AN OPTICAL MICROSCOPE OLYMPUS CX31 OLYMPUS CORPORATION TOKYO JAPAN AND A SERIES OF IMAGES AT DIFFERENT TIME INTERVALS WERE CAPTURED BY AE ADOBE AFTER EFFECTS CS4 ADOBE SYSTEMS INCORPORATED SAN JOSE CA USA IN A TYPICAL DRUG RELEASE EXPERIMENT 25 ML OF PBS RELEASE MEDIUM PH VALUE 7 4 OR SIMULATED GASTRIC UID 0 1 M HCL SOLUTION PH VALUE 1 0 WAS TRANSFERRED INTO A ASK AND THE DRUG LOADED MICROPARTICLES 50 MG WERE ADDED INTO THE ASK THE ASK WAS KEPT IN A SHAKING INCUBATOR AT 37 C WITH CONSTANT AGITATION 65 RPM AT CERTAIN TIME INTERVALS 1 ML OF THE RELEASE MEDIUM WAS PERIODATE OXIDATION OF DIOL AND OTHER FUNCTIONAL GROUPS 3 WITHDRAWN PERIODICALLY FROM THE ASK AND REPLACED WITH THE SAME AMOUNT OF FRESH RELEASE MEDIUM THE RELEASE MEDIUM WAS PASSED THROUGH A 0 45 M MEMBRANE LTER MILLIPORE SHANGHAI CHINA IN ORDER TO REMOVE INSOLUBLE MATTERS THE CONCENTRATION OF HYDROCORTISONE WAS DIRECTLY MEASURED BY UV VIS SPECTROSCOPY SPECTRAMAX M5 MOLECULAR DEVICES SILICON VALLEY CA USA AT A WAVELENGTH OF 247 NM FOR THE DETERMINATION OF LYSINE CONCENTRATION DUE TO ITS NON OBVIOUS ABSORPTION PEAK IN THE ULTRAVIOLET AND VISIBLE LIGHT AREAS A NINHYDRIN METHOD WAS ADOPTED FOR LYSINE QUANTI CATION 47 48 BRIE Y SAMPLES OF RELEASING MEDIUM 0 5 ML AND NINHYDRIN SOLUTION 0 5 ML WERE PUT IN TUBES AND HEATED IN A BOILING WATER BATH FOR 10 MIN AFTER HEATING THE TUBES WERE FULLY COOLED IN AN ICE BATH THEN 2 5 ML OF 50 ALCOHOL WAS ADDED INTO EACH TUBE AND THOROUGHLY MIXED WITH A VORTEX MIXER FOR 15 S THEN 200 L OF THE REACTION MIXTURE WAS TRANSFERRED INTO QUARTZ 96 WELL PLATES AND THE LYSINE CONCENTRATION WAS DETERMINED BY MEASURING THE ABSORBANCE VALUES AT 570 NM 3 RESULTS AND DISCUSSION 3 1 PARTICLE FORMATION PROCESS SOLUTIONS COMPOSED OF HPMCP SCHEME 1A AS THE CARRIER MATERIAL HYDROPHOBIC HYDROCORTISONE SCHEME 1B OR HYDROPHILIC LYSINE SCHEME 1C AS THE MODEL DRUG AND ETHANOL WATER MIXTURE AS THE SOLVENT WERE ATOMIZED INTO UNIFORM DROPLETS AND DIRECTLY ASSEMBLED INTO UNIFORM MICROPARTICLES SCHEME 1D G VIA SPRAY DRYING AT A SOLID CONTENT OF 2 5 W V A HYDROCORTISONE TO HPMCP MASS RATIO OF 0 025 1 AND A DRYING TEMPERATURE OF 155 C UNIFORM DISCRETE AND DIMPLED SPHERICAL MICROPARTICLES OF 57 9 M IN SIZE FIGURE 1A WERE OBTAINED BY USING AN ETHANOL WATER MIXTURE OF 1 4 VOLUME RATIO AS THE SOLVENT THE SURFACES OF THESE MICROPARTICLES ARE SMOOTH AND DENSE FIGURE 1A INSET INDICATING THE DRUG MOLECULES ARE ENCAPSULATED INSIDE THE HPMCP MATRIX THE DEFORMATION OF SPHERICAL DROPLETS INTO DIMPLED MICROPARTICLES ORIGINATES FROM SURFACE TENSION GRADIENTS OF DRYING DROPLETS IN GENERAL THE DROPLET AIR LIQUID INTERFACE RECEDES WHILE DRYING SCHEME 1D AND IS GRADUALLY CONCENTRATED BY THE PRECURSOR INGREDIENTS THAT DIFFUSE INWARD ACCORDING TO FICK S LAW 49 WHEN THE INGREDIENTS REACH SATURATION THE DROPLET SURFACE WILL BE SOLIDI ED TO FORM A SHELL AND STOP SHRINKING SCHEME 1D E ON THE OTHER HAND DRYING INDUCES TEMPERATURE GRADIENTS INTERIOR INTERFACE TEMPERATURE MAKING SURFACE TENSION DIFFERENCES INTERIOR EXTERNAL AND PREFERENTIAL EVAPORATION OF ETHANOL LEAVES BEHIND MORE WATER FURTHER ENLARGING THE SURFACE TENSION DIFFERENCES THUS CREATING INWARD CAPILLARY FORCES SCHEME 1E THE SOFT NATURE OF THE HPMCP POLYMER WITH REMAINING WATER SOLVENT MAKES THE SHELL UNABLE TO WITHSTAND THE CAPILLARY FORCES LEADING TO SHAPE DEFORMATION SCHEME 1F AND SUBSEQUENTLY DIMPLED OR CRUMPLED MICROPARTICLES SCHEME 1G SCHEME 1 THE MOLECULAR STRUCTURES OF THE HPMCP POLYMER A THE MODEL DRUGS HYDROCORTISONE B LYSINE C AND A REPRESENTATION OF THE FORMATION PROCESS D G OF THE PHARMACEUTICAL MICROPARTICLES VIA MICRO UIDIC SPRAY DRYING PERIODATE OXIDATION OF DIOL AND OTHER FUNCTIONAL GROUPS 4