Biopharmaceutical Classi Cation System Of Apis Biology Essay

Active pharmaceutical ingredients are classified harmonizing to the Biopharmaceutical classii¬?cation system into four categories based on drug solubility and GI permeableness ( Table 1 ) . This categorization is widely used during the drug development procedure to inform the path taken to explicate a drug into a dose signifier. Within the BCS, category II is dei¬?ned as drugs of low solubility and high permeableness and is non-polar ( G.L. Amidon 1995 ) . In fact, most recent developed drugs have hapless H2O solubilitysince they have hydrophobic belongings ( Vasconcelos,2007 ) ; in other words, these drugs easy permeate the GI membrane since the GI membrane has hydrophobic ( lipotropic ) constituents ; in contact, these drugs lack the ability to be soluble in hydrophilic GI fluid which accordingly affects the bioavailability of these drugs ( Streubel,2006- Ohara 2005 ) . Poor bioavailability is an of import issue as it will act upon the concluding merchandise efficaciousness and increase its side effects ; furthermore, it may increase the development times and cost. Therefore, betterment of the solubility of the category II drugs is a important challenge to pharmaceutical industry. Recently, different attacks have been tried to increase the solubility of category II drugs, and one of these attacks which is being intensively studied is solid scatterings.

( Table 1 ) Biopharmaceutical classii¬?cation system of APIs:

Solid scatterings are one of the most promising techniques for bettering the solubility, soaking up and the efficaciousness of drugs. Furthermore, for elucidation a comprehensive definition of solid scattering ; is the scattering of one or more active pharmaceutical ingredients ( APIs ) which have hapless H2O solubility in a bearer or matrix at solid province ( e.g. polymers ) which has high H2O solubility ( Chaudhari.P.D,2006 -Dhirendra, K,2009 ) ; hence, it is a solid mixture of hydrophobic drugs ( APIs ) and hydrophilic bearer ( polymers ) . Furthermore, legion surveies on readying of solid scatterings have been published found that the solubility of hapless H2O soluble drugs has been significantly improved by production of solid scatterings and in turn drug disintegration rate and bioavailability. However, the stableness is one of the restrictions that faced the solid scattering which need to be solved and it will be issue that we will concentrate on in the present research.


One of the assuring techniques to better the bioavailability of hapless soluble drugs ( Class II ) is to utilize solid scatterings as a drug bringing system which can be obtained by several methods ; nevertheless, choosing one of these methods is really of import which dependon the characters and the public presentation of the drugs and bearers. The three major methods are: runing methods, solvent vaporization methods, and runing solvent methods ( Vilhelmsen, T.,2005 ) . Furthermore, this fabricating procedure of solid scatterings can be divided into several techniques as shown in ( Figure 1 )

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( Figure 1 ) Fabrication procedures of Solid Dispersions. ( Ki Taek Kim 2011 )

Choice of the API and the bearer ( polymer ) should be suited with each other and it is really of import issue ; due to the disintegration behaviour of the polymer is a sphere factor that affects the solubility and disintegration rate of category II drugs which is indissoluble in H2O. Furthermore, drug-polymer interactions may impact the drug release. Therefore, drug-polymer system should be carefully considered when fixing solid scattering ( Ki Taek Kim2011 ) ( Fumie Tanno 2004 ) .

The polymer used in this research was Hydroxypropyl Methylcellulose Acetate Succinate HPMC-AS ( LF class ) is a cellulous derived functions white to yellowish formless pulverization and has physiological compatibility ; moreover, it contains acetyl groups which have hydrophobic belongings and succinoyl groups which have hydrophilic belongings are introduced into hydroxyl groups of HPMC anchor as shown in ( Figure 589 ) which offer of import characters to the polymer.In other words ; the organic acids ( e.g. acetic and succinic acids ) help to speed up the drug release and to better the disintegration rate due to Amphiphilic belongings.

Figure 589, HPMC-AS polymer ( taken from supplier, Shin-Estu, Japan )

Furthermore, HPMC-AS has a alone characteristic it can be dissolved in buffers of assorted PH values which can be controlled by altering the classs of HPMC-AS ( Obara, S 1999 ) ; in other words, it can be controlled by altering the ratio of ethanoyl group and succinoyl groups and the atom sizes as There are six classs of HPMC-AS which are divided harmonizing to their atom size and the chemical permutations degrees. However, HPMC-AS is surface active bearer which revealed that it may assist to better the stableness of formless solid scattering by suppression the nucleation and agglomeration, hence it may forestall re-crystallization of the solid scattering and go physical and chemical stalls. ( Pouton 2006 )

As we know the formless signifier is non stable comparing to crystalline signifier because the inclination of the formless signifier to change over into crystalline signifier during bring forthing of solid scattering or storage ; hence, the disintegration rate and stableness of solid scattering would bit by bit diminish during storage clip, therefore impacting the bioavailability of the drug and limits its usage. However, the present survey may show extension in the stableness of formless signifier significantly by fixing solid scattering of Felodipine with HPMC-AS.

Therefore, the purpose of the present research is to detect comparing of formless solid scattering of Felodipine/HPMC-AS ( API/Polymer ) that produced by utilizing two different pharmaceutical techniques the first 1 is category as runing methods ( Hot Melt Extrusion ) and the 2nd 1 is category as runing solvent methods ( Spray Drying ) ; furthermore, to find if these techniques will impact the solubility of the category II drug ( e.g. Felodipine ) and whether they will act upon the disintegration rate and the bioavailability of the drug ; moreover, to measure if these techniques will bring forth stable merchandises by utilizing HPMC-AS due to the formless signifiers are known to hold low stableness than crystalline signifiers stableness. Therefore, the belongingss of preparations were studied by utilizing thermic and analytical techniques which are used to measure the physicochemical word picture and the morphology of merchandises ; for illustration, differential scanning calorimetry ( DSC ) , thermo-gravimetric Analysis ( TGA ) and X-ray diffraction ( XRD ) ; in add-on, disintegration and stableness survey.

The ground for choosing these two techniques is because they are the most commercial graduated tables present in pharmaceutical industry for bring forthing solid dispersion.In add-on, for doing comparing between both of them and make up one’s mind the best 1 for solid scattering harmonizing to the consequences.

Hot Melt Extrusion

The simple definition of runing methods is when the physical mixture of drug and bearer is heated at specific temperature until melted so the liquefied mixture is cooled and hardening into coveted form.

In other words, Hot Melt Extrusion ( HME ) is basically the same as the thaw method ; farther, this procedure is widely used inrubber, plastic, and nutrient industry. Recently, HME has found its manner to come in the pharmaceutical industry and has been applied for fabricating a assortment of dose preparations such as pellets, granules, tablets, implants, transdermic systems and suppositories. Therefore, HME in pharmaceutical significance is the procedure that change overing a natural stuffs ( i.e. drugs, polymers or both of them ) into a merchandise holding unvarying form and denseness by coercing these stuffs to go through through barrel country which has desired temperature so determining the extrudes by utilizing specific dice.

For more understanding HME procedure, HME can be divided into four stairss: ( 1 ) eating mixture: in this measure the pulverization mixture of API and polymer is feeding into heating barrels manually or by utilizing auto-feeder after proper commixture ( 2 ) conveyance of mass and entry into the dice: this is the nucleus of HME, because the physical mixture will transform into liquefied mixture ( homogeneous solid scattering ) of drug and polymer after intermixing inside the warming barrels by a individual prison guard or co-rotating twin prison guard ( revolving in the same way ) that in bend compress, mix and melt the mixture stuffs ( 3 ) flow throw the dice: the liquefied mass pumps through the dice which forms the extrudates into the needed form ( 4 ) issue from the dice and down-stream processing: extrudates will be cooled so the aggregation will be determining to suit the needed utilizations ( e.g. tablets, pellets or movies ) .

However, in this survey we used twin screw extruder because it possess many advantages over individual prison guard ; for illustration: shorter abode clip between ( 5-10 mins ) hence avoiding overheating, superior commixture because it consists of three subdivision ; feeding subdivision, runing subdivision and metering subdivision as shown in ( Figure ) , versatility as the operating parametric quantities can be adjusted easy during operation procedure. ( Sarika Madana,2012 )

Hot Melt ExtrusionHot Melt Extrusion procedure has many advantages which helped it to turn rapidly in pharmaceutical applications. One of the major advantages compared to the traditional procedure is free dissolver ( i.e. anhydrous ) procedure and O may be omitted about wholly ; hence, suited for wet and O sensitive drugs so prevent hydrolysis and oxidization ; in add-on, there is no needed for drying measure and the operating parametric quantities can be easy changed during processing, Furthermore, the process is a fast uninterrupted, one-step and simple procedure ; besides, HME provides good distributive and dispersive commixture which give homogeneous distribution of drug within bearer ( i.e. polymer ) . Furthermore, it improved merchandise quality, reduced merchandise variableness and the abode clip is short ( 2-10 mins ) doing short thermic exposure of API permits processing of heat sensitive drugs. Additionally, HME helps to dissembling acrimonious gustatory sensation of some APIs by utilizing some polymers ( e.g. HPMC ) . In add-on, it enhances the bioavailability by bettering the disintegration rate of ailing H2O soluble drugs by organizing formless solid scattering of drug in the polymer. Furthermore, it has good output per centum between ( 55-75 % ) . Finally it is green engineering as no organic dissolver is needed and are readily scalable. ( Sarika Madana,2012 ) ( JorgBreitenbach 2002 ) ( E.I. Keleb 2004 ) ( LienSaerens 2012 )

However, HME besides has certain challenges ; for case, high procedure cognition required, high procedure temperature, recycling of stuffs is hard, cleaning hard, high energy input, high initial cost ; nevertheless, all these restrictions can be overcome one time the coveted parametric quantities and the procedure are firmed up. ( Sarika Madana,2012 ) ( JorgBreitenbach 2002 )

The stairss of production solid scattering utilizing Hot Melt Extrusion is described in ( Figure 2 )

Spray Drying

The 2nd technique used to fix solid scattering in this survey is spray drying which is a technique transforming liquid or slurry formations ( e.g. solution, suspension or emulsions ) , which are obtained by fade outing APIs and excipients ( e.g. polymer ) in a suited dissolver ( e.g. methyl alcohol or propanone ) , into dry powdered signifiers. ( Masters 1985 ) . Furthermore, spray drying is one of the promising techniques which is widely used in pharmaceutical industry to increase the solubility and disintegration rate by fixing micro-particles of drug with polymer.

Spray drying process consist of four chiefly stairss as shown in ( Figure 3 ) : ( 1 ) eating: after readying the feedstock in flask so the feedstock is presenting into the spray drier chamber at specific feeder velocity ( 2 ) atomisation: is the bosom of any spray drying machine it helps to make the best status for vaporization by interrupting the solution up into little droplets which have diameter less than 100Aµm ( 3 ) droplets-gas contact and drying measure: the atomized droplets reach the chamber so these droplets will be straight in contact with hot gas ( e.g. Nitrogen which is inlet gas ) supplying heat required for rapid vaporization of more than 95 % of H2O from the droplets in merely a fraction of a 2nd after that as the dissolver is removed from the dried droplets a high viscousness membrane signifiers on the exterior of the droplets due to the movie organizing belongings of HPMC-AS. Furthermore, the drying measure is really critical measure as choosing proper conditions ( e.g. recess and mercantile establishment temperature, gas flow rates and atomizer force per unit area ) consequence straight on the velocity of taking dissolver from the droplets ( 4 ) separation: the dried droplets will be separated harmonizing to its size into different countries called cyclones or by utilizing filter system which called scrubber ; for illustration, Cyclon-1 will roll up all right atoms and Cyclon-2 will roll up the really all right atoms ; furthermore, the last chamber called Scrubber will roll up ultra-fine atoms. Therefore, the coveted atoms size is selected harmonizing to the type of the dose signifier.

Furthermore, the grounds that make spray drying an attractive procedure presents due to it offers many advantages. For case, it is a single-step, closed-system and uninterrupted procedure as it is to the full automated control system that allows direct monitoring and commanding parametric quantities procedure at the same time, besides it can be designed to have any capacity required ( i.e. feeding rates can be range from a few lbs per hr to over 100 dozenss per hr ) that mean it is scalable procedure scope from small-scale production to large-scale commercial production ; in add-on, the designs of spray drier give it ability to run into the assorted merchandise specifications ( i.e. the feedstock can be solution, slurry, paste, suspension, gel, emulsion or run signifier ) . It is suited with both heat-sensitive and heat-resistant merchandises because the existent drying clip of a droplet is really short as the dissolver evaporated in less than few seconds it helps avoiding overheating. Furthermore, the dried merchandise can be about spherical atoms in the signifier of pulverization, agglomerates or granules with big surface country and unvarying atom size depending on the selected parametric quantities ( e.g. feeding rate, recess and outlet temperature of air, atomiser force per unit area, viscousness and the physical and chemical belongingss of the feedstock ) . ( Dwayne T 2008 ) ( Gharsallaoui A 2007 ) ( Renata Jachowicz 2008 ) ( R. P. Patel2009 ) ( Patel Tejas2012 ) ( Pierre Lebrun 2012 )

However, spray drying besides has certain challenges ; for case, the equipment is really bulky and expensive, besides low output per centum between ( 30-55 % ) . Furthermore, it has limited in bring forthing atoms with complex morphologies. Furthermore, big volumes of het air base on balls through the Chamber without reaching a droplet ; hence, its thermic efficiency is low. ( R. P. Patel2009 ) ( Patel Tejas2012 )



Felodipine was purchase from Hubei MaxSource Chem Co. , Ltd. ( Wuhan City, China ) and the stuff that has been used as polymer, which has two generic names was Hydroxypropyl Methylcellulose Acetate Succinate, JPE or Hypromellose Acetate Succinate, NF ( HPMC-AS: Shin-Estu AQOATA® ) with class ( LF ) as shown in ( Table 1 ) , was obtained from ( Shin-Estu Chemical Co. , Tokyo, Japan ) . HPMC-AS is aqueous enteral coating agent and non-toxic stuff which has been used in pharmaceutical industry for many old ages. Acetone was purchased from Sigma-Aldrich Company Ltd. Gillingham, UK. All chemicals were used straight without farther purification.

Table 1, Grades of HPMC-AS harmonizing to Accetyl and Succinoyl Group content


Preparation of Solid Dispersion

Hot-melt bulge

Three batches of drug and polymer mixture were prepared. Batch ( No. 1 ) contains Felodipine/HPMC-AS 30 g ( 1:1 w/w ) was assorted in a plastic bag for 10 min, bath ( No. 2 ) contains Felodipine/HPMC-AS 30 g ( 1:2 w/w ) was assorted in a plastic bag for 10 min and batch ( No. 3 ) contains Felodipine/HPMC-AS 40 g ( 1:3 w/w ) was assorted in a plastic bag for 10 min after that all these batches extruded utilizing a hot thaw extrusion,16 mm co-rotating twin screw extruder ( Thermo Fisher Scientific, Germany ) which has production scope between ( 0.2-5 kg/h ) . In add-on, the extruder barrel was divided into zones ( 2-10 zones ) ; furthermore, the temperature of each zone and dice can be controlled individually. Furthermore, the procedure parametric quantities were fixed for whole batches. The feeding rate into the thaw extruder was about ( 4.5-5 g/m ) and was manually due to little sum of batches. Screw velocity was 100 revolutions per minute. Furthermore, the temperature sequence was shown in ( Table 2 ) .























Table 2, Temperature sequence in hot thaw bulge for processing

In add-on, we should wait about ( 5-10 min ) between each batch to be certain all stuffs had been extruded, due to the abode clip in the extruder was about ( 5-7 min ) , to forestall taint between batches ; furthermore, the first merchandise of each batch should be discarded. Finally, the thaw extrudate was air cooled on a conveyer belt.

Shin-Estu Company supports us with cleaning stuff which is particular for HPMC polymer ; hence, the cleansing issue becomes easier. However, the Temperature sequence for Cleaning was differ from the temperature of processing as was shown in ( Table 3 )























Table 3, Temperature sequence in hot thaw bulge for cleansing

Spray Drying

Three batches of drug and polymer mixture were prepared. Batch ( No.1 ) contains Felodipine/HPMC-AS 5 g ( 1:1 w/w 2.5/2.5 w/w ) was dissolved in 200 milliliter of propanone, bath ( No.2 ) contains Felodipine/HPMC-AS 7.5g ( 1:2 w/w 2.5-5 w/w ) was dissolved in 200 milliliter of propanone and batch ( No.3 ) contains Felodipine/HPMC-AS 10g ( 1:3 w/w 2.5-7.5 w/w ) was besides dissolved in 200 milliliter of propanone ; in other words, Felodipine was dissolved in 100ml propanone and HPMC-AS was dissolved in 50ml propanone and was so stirred utilizing magnetic scaremonger until completely disintegration both solutions mixed together so the concluding 50 milliliter propanone was added. After that all batches spray dried utilizing research lab Spray Dryer ( LU-228 AdvancedA® Labultima, Maharashtra, India ) which accept solvent/aqueous Feeds with co-current Spray and has twin cyclons connected straight with N2 Inert Loop the ground for utilizing Nitrogen as atomising gas in spray drying procedure because propanone is flammable organic dissolver and N is considered as an recess gas. Furthermore, the undermentioned spray drying conditions shown in ( Table 4 ) were used:

Inlet Temp.


Feed pump flow rate

2 ml/min

Outlet Temp.

35 EsC


5 %

Inlet High

100 EsC

Log interval

60 sec

Outlet High

45 EsC

Atomization Pressure

00.50 Kg/cm3

Aspirator Flow rate

50 Nm3/hr


Up to +50 millimeter

Table 4, Spray Drying Conditionss

Finally, spray dried pulverizations were weighted and collected in capped glass phials.

Preparation of Physical Mixture

For comparing with solid scattering physical Mixtures of Felodipine/HPMC-AS with three different ratio ( 1:1 w/w ) , ( 1:2 w/w ) and ( 1:3 w/w ) were prepared by blending for 10 min in a howitzer and stamp.

Dissolution surveies

The survey of in vitro disintegration trial was performed utilizing two types of disintegration medium the first medium was phosphate buffer solution PH 6.8 and the other 1 was Phosphate Buffer solution PH 6.8 with 1 % Na dodecyl sulphate SDS as a wetting agent ; nevertheless, both mediums should maintained at 37 A± 5 EsC to imitate the nature of bowel aˆ¦ … .Consists of six vass and the paddle velocity was set at 50 revolutions per minute. Furthermore, pulverization samples of solid scatterings ( 1:1, 1:2 and 1:3 ) produced by HME and Spray drying tantamount to 25 milligram of Felodipine were added to 900 milliliters disintegration medium which maintained at 37 A± 5 EsC. In add-on, the physical mixtures ( 1:1, 1:2 and 1:3 ) were studied and added to 900ml disintegration medium besides to compare the consequences with the consequences of solid scatterings. Furthermore, 5ml samples were withdrawn harmonizing to this times intervals from each vas ( 5, 10, 15, 20, 30, 45, 60, 75, 90, 135, 345, 405 min ) and filtered through 0.45 Aµm syringe filters ( MillexA®HA, MCE membrane, Millipore co. , Carrigtwohill, Ireland ) so replaced with an equal volume of fresh media. Then the sum of drug release was determined utilizing ( UV-Vis ) spectrometry at wavelength 364 nm aˆ¦ .

Thermal surveies

Thermohydrometric Analysis ( TGA )

The survey was performed on samples of Felodipine and HPMC-AS individually by utilizing TGA Q5000A® system ( TA instruments Inc. , New Castle, USA ) to understand and find the decomposition temperature of the API and polymer. About 5-10 milligram samples were heated in unfastened Pt pans from 10 EsC to 500 EsC, and so the experimental informations were collected and analyzed utilizing TA Universal Analysis 2000 package Version 4.7A ( TA instruments Inc. , New Castle, USA ) . Nitrogen was used as a purging gas at a flow rate of 25 ml/min.

Figure 400, Thermogravimetric Analysis ( TGA ) Q5000

Differential Scanning Calorimetry ( DSC )

Differential Scanning Calorimetry experiments were used to find and mensurate the changing in thermic belongingss ( e.g. glass passage temperature and runing point ) of the prepared solid scatterings and physical mixtures by utilizing DSC Q2000A® instrument ( TA instruments Inc. , New Castle, USA ) . About 2-5 milligram Samples were accurately weighed into aluminium pans with a pinhole palpebra and hermetically crimped. The samples were heated under N environment in a temperature scope between 25 EsC to 250 EsC with heating rates of 5EsC/min. Nitrogen was used as a purging gas at a flow rate of 50 ml/min.

Figure 500, Differential Scanning Calorimetry ( DSC ) Q2000

Analytic method

X-ray pulverization diffraction ( pXRD )

The X-ray pulverization diffraction was performed utilizing D8- ADVANCEA® ( Bruker AXS Inc. , Madison, USA ) . The samples were placed on the sample holder ( 0.5 mm deep ) and the sum needed was about 500 milligrams to busy the holder and organize a thin bed of the sample pulverization. The X ray was obtain by a Cu radiation beginning Cu KI± ( I»=1.54056 A ) with generator electromotive force of 40 kilovolts and current of 40 ma. Furthermore, the samples were scanned on uninterrupted sensor scan manner over the diffraction angle ( 2I? ) scope of 2 Es & lt ; 2I? & lt ; 60Es ( with a 2I? measure size of 0.01220Es and at scan velocity of 1s/step ) at ambient status, while sample rotary motion was away. Finally, the consequences were analyzed and collected utilizing EVA DIFFRACplusA® package ( Bruker AXS Inc. , Madison, USA ) .

Stability survey

Approximately 1-4 g sample size of each of the solid scattering was collected in capped glass bottles and placed indoors controlled humidness and temperature stableness room ( Memmert HPP-108A® , Memmert Co. Germany ) with pre-equilibrated status to 40EsC/75 % RH. During the class of survey a little sum of samples were withdrawn for each bottle at specific clip interval ( i.e. each 10 yearss ) for scrutiny and word picture by utilizing DSC and pXRD before replace the bottles back into the stableness room.



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