The research presented in this thesis focuses on the application of a pharmaceutical engineering, spray-drying method, affecting the usage of a co-solvent system and potentially a procedure foil, for illustration, ammonium carbonate or ammonium hydrogen carbonate, to bring forth atoms suited for inhalation drug bringing, peculiarly in dry pulverization inspiration bringing devices.
This engineering is late anticipated for different drug compounds/excipients, as it has advantages over current engineerings in that it involves a simple one-step atom technology method and produces microparticles suited for inspiration. Previous research workers have conducted several surveies to research the possible production of atoms suited for inspiration utilizing this fresh method, and these tests were successful, for illustration budesonide ( McDonald, 2005 ) , sodium cromoglicate ( Nolan, 2008 ) and proteins ( N & A ; iacute ; & A ; Oacute ; g & A ; aacute ; in, 2008 ) . However, the feasibleness of utilizing this method to bring forth inhalable atoms of antitubercular drugs and full physicochemical word picture of the cured atoms had non been antecedently described in the literature.
Therefore, it was of import to look into the possible application of this engineering on antitubercular agents and to characterize the produced atoms in comparing to the unrefined stuffs. In add-on, this work may be considered as a base for new method for production of porous atoms through spray drying of ammonium salts of drug compounds. Five antitubercular drugs: p-aminosalicylic acid ( Chapter 3 ) , pyrazinoic acid ( Chapter 4 ) , isoniazid, rifampicin and pyrazinamide ( Chapter 5 ) , every bit good as four acidic drugs: benzoic acid, salicylic acid, sulfamethizole and Sulamyd ( Chapter 4 ) and five ammonium salts, viz. ammonium salt of p-aminosalicylic acid ( Chapter 3 ) , pyrazinoic acid, benzoic acid, salicylic acid and Sulamyd ( Chapter 4 ) , were selected for analysis. The antitubercular drugs were used to analyze the feasibleness of developing atoms of antitubercular drugs suited for lung bringing ( Chapter 5 ) . On the other manus, the series of acidic drugs were selected to look into the potency of treating a series of similar compounds into fresh solid-state and to place possible similarities in chemical features that could be correlated to novel solid-state production.The work in this thesis focuses chiefly on the consequence of altering spray drying parameters/conditions on the physicochemical and morphological features of the cured spray-dried atoms.
Drug compounds were spray-dried entirely or the procedure foil, ammonium carbonate, was incorporated into the preparation. Tajber ( 2005 ) , McDonald ( 2005 ) and Nolan ( 2009 ) had antecedently shown that incorporation of ammonium carbonate did non impact the chemical features of spray-dried stuffs. However, in the current work, a fresh solid-state was obtained by spray drying of p-aminosalicylic acid either utilizing ammonium carbonate or ammonium hydrogen carbonate, irrespective of the dissolver used, as shown in Chapter 3.A farther point of involvement illustrated in Chapter 4 is that production of the new solid sate signifier was besides noticed upon utilizing other acidic drugs benzoic acid, salicylic acid, pyrazinoic acid and Sulamyd, but no distinguishable alterations in footings of DSC or FTIR was shown when sulfamethizole was spray-dried with the procedure foil, ammonium carbonate. In add-on the thermic behavior and XRD form of spray dried sulfamethizole/ammonium carbonate was compared favorably with the findings reported by Nolan, ( 2008 ) for spray dried sulfamethizole/ammonium carbonate. Therefore, an in-depth survey into the physicochemical word picture of the solid-state of spray-dried acidic compounds/ammonium carbonate was undertaken.
A comparative survey between spray-dried and physical mixtures of acidic compounds/ammonium carbonate was besides undertaken to analyze the consequence of incorporation of ammonium carbonate or ammonium hydrogen carbonate, as a procedure foil, in the spray drying procedure.The solid-states of spray-dried ammonium salts were besides characterised in footings of thermal and elemental analysis. These surveies were considered of import in finding the solid-state features of spray-dried acidic compounds/ammonium carbonate and to look into the feasibleness of production of porous atoms of an acidic drug via spray drying of ammonium salts of tantamount compounds.Production of NPMPs of antitubercular drugs was investigated, where the consequence of the procedure variables of spray drying on the production of NPMPs was explored. Antitubercular drugs were spray dried alone or with excipients ( PVP or HP-?-CD ) ( Chapter 3 and 5 ) .
In add-on, selected spray-dried and micronised atoms of tantamount stuff were characterised in footings of physicochemical word picture and in vitro aerosolisation public presentation to find advantages of spray dried atoms for inspiration bringing. Micromeritic analysis included denseness and surface country measurings.Based on old treatment this chapter is divided into five subdivisions* Production of fresh solid province upon spray drying of acidic compounds* Spray drying of ammonium salts* Morphological features of cured atoms* Spray drying of active pharmaceutical ingredient/excipient combinations* Aerosolisation public presentation of spray dried atoms
6.2 Production of fresh solid-state upon spray drying of acidic compounds
As reported by Nolan, ( 2009 ) excipient-free nanoporous microparticles ( NPMPs ) of budesonide were produced with the inclusion of the pore-forming agent, ammonium carbonate. Briefly, Nolan, ( 2009 ) spray dried budesonide from 90 % ( v/v ) ethyl alcohol at an inlet temperature of 78 & A ; deg ; C. The entire solid concentration in solution was 1 % ( w/v ) . The ammonium carbonate was added in a concentration equivalent to 15 % of the entire weight of solids ( such that budesonide concentration in solution was 0.85 % w/v ) .
The pore-forming agent, ammonium carbonate, was expected to be volatilised ( volatilisation temperature 59 oC ) during the spray-drying procedure, which may in itself promote pore formation, through a type of “ blowing ” mechanism. As the spray drying procedure runing above the decomposition temperature of ammonium carbonate, it was expected that the ammonium carbonate is removed from the spray dried system with the fumes gases, hence bring forthing basically excipient-free NPMPs. It should be noted that Nolan, ( 2009 ) analysed spray dried budesonide/ammonium carbonate samples and budesonide natural stuff utilizing an ammonium hydroxide check kits ( Sigma-Aldrich, Ireland ) . The writers reported that the sum of ammonium hydroxide in spray dried budesonide/ammonium carbonate samples was below the bound of sensing of the check ( 1 % w/w ) .In another survey, Straub et al. , ( 2005 ) produced porous atoms of paclitaxel by spray drying a solution ( water/ethanol in ratio of 1:4 ) incorporating the drug, a water-soluble excipient such as Osmitrol and a pore-forming agent, ammonium hydrogen carbonate ( volatile salt ) . The H2O soluble excipient facilitates wetting of the drug atoms during reconstitution, provides proper osmolality to the dose signifier, and improves the storage stableness of the dry pulverization.
Similarly, the pore forming agent is volatilised and removed during processing.In add-on to the old surveies, Frenkel et al. , ( 1995 ) reported that ammonium salts undergo thermic decomposition with the formation of gaseous ammonium hydroxide. This decomposition can continue both in the solid stage by the warming of the dry salt in a watercourse of inert gas, and in the liquid stage by heating the solution of the salt. Decomposition of ammonium salts is employed in the industry for the distillment of ammonia-containing waste ( Frenkel et al. , 1995 ) .
Furthermore, ammonium carbonate decomposes into ammonium hydroxide, C dioxide and H2O at temperatures over 59 & A ; deg ; C. Similarly, ammonium hydrogen carbonate decomposes at 36 to 60 & A ; deg ; C into ammonium hydroxide, C dioxide and H2O vapour. Therefore, it is assumed that in a spray drying procedure runing above this temperature ammonium carbonate is removed, go forthing porous atoms to be collected in the drier.
The chemical constructions of budesonide ( the theoretical account drug compound used by Nolan, ( 2009 ) ) , p-aminosalicylic acid ( the theoretical account drug compound used in this work ) and ammonium salt of p-aminosalicylic acid are shown in Figure 6.1. Budesonide is a glucocorticoid, which has no acidic group ; hence, it is non possible to respond with ammonium hydroxide, which means ammonium carbonate will act in the solution as a free molecule and therefore the decomposition and remotion of ammonium carbonate during spray drying procedure is likely. On the other manus, p-aminosalicylic acid is an acidic compound, harmonizing to Merck Index, it has a pKa value of 3.25 and the pH of 0.
1 % aqueous solution of p-aminosalicylic acid is 3.5. Therefore, p-aminosalicylic acid has possible to respond with ammonium hydroxide. The construction of ammonium salt of p-aminosalicylic acid which was prepared by chemical reaction between ammonium hydroxide and p-aminosalicylic acid is shown if Figure 6.1c. This may explicate the ground behind production of excipient free atoms reported by Tajber ( 2005 ) and Nolan, ( 2009 ) utilizing ammonium carbonate, where the drug compounds used by Tajber ( 2005 ) and Nolan, ( 2009 ) did non respond with the procedure additives ; hence, the procedure additives were decomposed and removed during spray drying as the recess temperature used was higher than their decomposition temperature.
In contrast, in this work the theoretical account drug has the possible to respond with the procedure additives, which resulted in uncomplete remotion of the procedure linear and production of a new solid province signifier.Figure 6.1 – Structure of ( a ) budesonide ( B ) p- aminosalicylic acid ( degree Celsius ) ammonium salt of p-aminosalicylic acid
6.2.1 Stoichiometry of the PAS/ammonium carbonate spray-dried systems
The stoichiometric ratio of the solid province produced upon spray drying of PAS with ammonium carbonate or ammonium hydrogen carbonate could be 2:1:0.5 p-aminosalicylic acid: ammonium hydroxide: H2O. This was ab initio estimated from elemental analysis of the cured atoms from spray drying of a solution of p-aminosalicylic acid/ammonium carbonate or p-aminosalicylic acid/ammonium hydrogen carbonate, which gave elemental analysis consistent with this stoichiometric ratio. An ammonia check was undertaken for p-aminosalicylic acerb natural stuff and the spray dried complexs.
In instance of the natural stuff, the sum of ammonium hydroxide was below the bound of sensing of the check ( 1 % ) . On the other manus, the sum of ammonium hydroxide determined in the spray dried complex was about 5.8 % , which confirmed the stoichiometric ratio of the solid province as shown in Chapter 3. Water contents were besides determined by Karl Fischer titration.
The sum of H2O detected was ~2 % . This was consistent with the stoichiometric ratio of the cured atoms as shown in Chapter 3. Another verification of the stoichiometry of spray dried samples is TG analysis ; TG analysis revealed that the weight loss between 25EsC and 100EsC was about 7.6 % for the spray-dried complex. The loss of one ammonium hydroxide molecule and half H2O molecule corresponds to a loss of ~7.8 % by weight of p-aminosalicylic acid: ammonium hydroxide: H2O 2:1:0.5 when determined on a molecular weight footing.
Therefore, the weight loss registered in spray dried complexs is consistent with the loss of one molecule of ammonium hydroxide and half molecule of H2O.
6.2.2 Solid-state features of the acidic compounds/ammonium carbonate spray-dried systems
As shown in Chapter 3, the chemical nature of p-aminosalicylic acid was of import with regard to solid-state features of cured atoms, in peculiar productions of a new solid province upon spray drying with ammonium carbonate. Six different acidic compounds were spray-dried from ethanolic solutions of 90 % ( v/v ) ethanol 10 % ( v/v ) H2O ( Chapter 3 and 4 ) , production of a new solid-state upon spray drying with ammonium carbonate were reported for five of these compounds, with merely one compound ( sulfamethizole ) which gave DSC and FTIR scans similar to the get downing stuff upon spray drying with ammonium carbonate ( Chapter 4 ) .
The construction of the acidic compounds and their pKa values are listed in Table 6.1. Four out of six selected theoretical account drugs are carboxylic acids, with similar pKa values. These four compounds are similar in constructions ( aromatic carboxylic acids ) .
It was proposed that these compounds may potentially undergo similar interactions with ammonium carbonate which may lend to the alterations in solid-state of cured atoms.The solid-state of cured atoms from spray drying of acidic sulpha compounds/ammonium carbonate was dependent on the interaction between the sulfa drug and ammonium carbonate. The solid-state of spray-dried sulfacetamide/ammonium carbonate was altered upon spray drying and there were grounds of sulfacetamide /ammonium carbonate interactions detected by DSC and XRD analysis.
On the other manus, there was no interaction between sulfamethizole and ammonium carbonate as indicated by XRD, DSC and FTIR analysis and the solid-state of spray-dried sulfamethizole/ammonium carbonate was similar to unrefined sulfamethizole. Although both sulfa compounds have same pKa values, but they differ by permutation on the sulfanilamide construction, Sulamyd has acetyl group, while sulfamethizole has 5-methyl-1,3,4-thiadiazol group. Bearing in head that sulfonyl group is the acidic group in the construction, so the deficiency of interaction between sulfamethizole and ammonium carbonate possibly due to the presence of bulky group ( methyl thiadiazol ) which may impede the interaction. In add-on, aqueous solubility of Sulamyd ( 1 in 150 of H2O ) is much higher than that of sulfamethizole ( 1 in 2000 of H2O ) .
Serajuddin, ( 2007 ) reported that the construct of the pH of maximal solubility of certain compound ( pH soap ) plays a major function in acid-base reaction. The writer depicted the influence of solubility of the acid and its pKaon pH maxand accordingly on salt formation. Furthermore, an addition in solubility and lessenings in pKaof the acidic drug will diminish pH maxand hence, favour salt formation.
Consequently, it may be assumed that the potency of salt formation of Sulamyd ( reaction between Sulamyd and ammonium carbonate ) is higher than that of sulfamethizole. A farther point of involvement was the possibility of synthesis of ammonium salt of Sulamyd ( Chapter 4 ) , meanwhile it was non possible to fix sulfamethizole salt.Therefore, it could be concluded that the production of the fresh signifiers of drug compounds upon spray drying with ammonium carbonate was dependent on the interaction of the acidic drug compound with ammonium carbonate. This may explicate the consequences reported by Tajber, ( 2005 ) ; McDonald, ( 2005 ) and Nolan, ( 2008 ) that produced excipient free atoms by spray drying drug compounds with ammonium carbonate, as the drug compound used in their surveies has no possible to respond with ammonium carbonate. Consequently, ammonium carbonate was wholly evaporated upon spray drying.Table 6.1- list of molecular weights, constructions and pKa values of acidic drugs used in the undertaking.
|p- Aminosalicylic acid||153.13||3.25||1 in 500 of H2O|
|4.19||1 in 300 of H2O|
|Salicylic acid||138.1||3||1 in 460 of H2O|
|2.92||soluble in cold H2O|
|Sulfacetamide||214.24||5.4||1 in 150 of H2O|
|Sulfamethizole||270.33||5.4||1 in 2000 of H2O|
6.2.3 Stoichiometry of the acidic compounds/ammonium carbonate spray-dried systems
As shown in Chapter 4, a new solid province was recovered upon spray drying of benzoic acid, salicylic acid, pyrazinoic acid and Sulamyd with the procedure linear, ammonium carbonate, as confirmed by DSC, FTIR and XRD.
Elemental analyses of some spray dried acidic compound with ammonium carbonate are shown in Table 6.2. Elemental analysis of spray dried complexs showed that the stoichiometric ratio of the cured atoms could be 2:1 acid: ammonium hydroxide. It should be noted that H2O contents of spray dried complexs were under the bound of sensing ( 1 % ) .It could be concluded that harmonizing to elemental analysis the possible stoichiometry for these systems could be 2 molecules of acid: 1 molecule of ammonium hydroxide.On the other manus, there were no differences in elemental analysis of spray dried sulfamethizole/ammonium carbonate in comparing with the unrefined stuff. This was consistent with the consequences of DSC and XRD of the spray dried sulfamethizole/ammonium carbonate, which showed that there were no important alterations in the solid province of sulfamethizole upon spray drying with ammonium carbonate.Table 6.
2- Elemental analysis of different acidic compounds systems.
|Benzoic acid unprocessed stuff||68.87||4.90||0||0|
|Spray dried benzoic acid/ammonium carbonate 80:20||64.
|Spray dried benzoic acid/ammonium carbonate 71:29||64.23±0.25||5.96±0.02||5.
|Spray dried benzoic acid/ammonium carbonate 66:34||64.19±0.20||5.95±0.04||5.47±0.
|Spray dried benzoic acid/ammonium carbonate 50:50||64.22±0.16||5.93±0.01||5.38±0.15||0|
|Benzoic acid: ammonium hydroxide 2:1 ( Calculated )||64.
|Salicylic acid unprocessed stuff||60.87||4.
|Spray dried salicylic acid/ammonium carbonate 80:20||57.36±1.56||5.02±0.33||5.03±0.40||0|
|Spray dried salicylic acid/ammonium carbonate 70:30||57.
|Salicylic acid: ammonium hydroxide 2:1 ( Calculated )||57.53||4.82||4.79||0|
|Sulfamethizole unprocessed stuff||39.
|Spray dried sulfamethizole/AC 95:5||39.
|Spray dried sulfamethizole/AC 90:10||39.68±0.07||3.70±0.
|Spray dried sulfamethizole/AC 80:20||39.
6.3 Spray drying of ammonium salts
Frenkel et al. , ( 1995 ) reported that ammonium salts undergo thermic decomposition with the formation of gaseous ammonium hydroxide.
Additionally, Chuck and Zacher ( 2000 ) reported that an aqueous solution of ammonium nicotinate can be converted to nicotinic acid by spray drying. Out of six acidic compounds selected for this work, merely sulfamethizole did non demo any interaction with ammonium carbonate, and it is neither available nor possible to fix its ammonium salt. For the other compounds, ammonium salt was either prepared or purchased. Ideally, uniform and porous atoms within the size scope of 2-5µm are desirable for inspiration systems. The cured atoms from spray drying of ammonium salts of both p-aminosalicylic acid and pyrazinoic acid have a size scope of approximately 1-10µm as estimated from several SEM micrographs ; they are unvarying, somewhat porous spherical agglomerates of atoms. Unfortunately, it was non possible to analyze the existent morphological features of spray-dried ammonium salts of benzoic acid and salicylic acid due to the usage of vacuity during the coating and visual image procedure. The porousness of atoms could be due to decomposition of ammonium salt and release of ammonium hydroxide.
This was confirmed by extended surveies on spray-dried ammonium salt of p-aminosalicylic acid, which showed that the solid-state of spray-dried salt at low recess temperature ( 78 & A ; deg ; C ) was different from either acid or salt signifiers of p-aminosalicylic acid.Elemental analyses of spray dried ammonium salt of p-aminosalicylic acid showed that the recess temperature affected the chemical composing of the cured atoms ( Table 6.3 ) . The nitrogen content of the cured atoms was decreased by increasing recess temperature. This could be due to partial decomposition of the salt upon spray drying and release of ammonium hydroxide.
It should be noted that the ability of ammonium salts to undergo thermic decomposition is good known ( Frenkel et al. , 1995 ) .Table 6.3- Elemental analysis of PAS and PAS salt systems
|Sample||Analysis % w/w|
|PAS ammonium salt||Calculated||49.41||5.
|Spray dried ammonium salt at 78EsC||Found||50.34±0.07||5.57±0.
|PAS ammonium salt spray-dried 120EsC||Found||52.
In add-on, other ammonium salts besides showed differences in solid-state upon spray drying, as confirmed by XRD and DSC scans of spray-dried salt, this could be attributed to decomposition of the ammonium salts upon spray drying.
Furthermore, spray drying of a solution of the ammonium salt of p-aminosalicylic acid at higher temperature ( 130EsC ) resulted in spherical atoms and sums of microcrystalline atoms, which gave elemental analysis, DSC and powder-XRD scans consistent with p-aminosalicylic acid. This was confirmed by elemental analysis, which showed that there was no difference between the spray-dried salt and p-aminosalicylic acid. This compares favorably with the consequences of spray drying of ammonium nicotinate presented by Chuck and Zacher ( 2000 ) who prepared pure nicotinic acid by spray drying of ammonium nicotinate.
These findings are utile in footings of production of porous atoms suited for inspiration, where atoms, suited for inspiration, may be obtained by readying of ammonium salts of chemotherapeutic agents, followed by spray drying of the salt utilizing spray drying method described earlier.
6.4 Morphologic features of cured atoms
The work in this thesis includes spray drying of 15 drug compounds, two excipients and mixture of different antitubercular drugs with excipients. Of these compounds, benzoic acid, salicylic acid and their salts are sublimable, so it was non possible to visualize their spray-dried atoms.p-aminosalicylic acid and its salt ( Chapter 3 ) , ammonium salt of pyrazinoic acid ( Chapter 4 ) , PVP, HP-?-CD and different antitubercular/ excipients ( Chapter 5 ) were successfully processed into porous atoms as a consequence of utilizing spray drying procedure.Three solvent systems, viz.
ethanol: H2O, ethyl alcohol: H2O: ammonium carbonate and methyl alcohol: H2O: ammonium carbonate were successfully used in this thesis to bring forth porous atoms of hydrophobic compound ( p-aminosalicylic acid ) . As shown in Chapter 3, the pick of these solvent systems was based on the findings reported by McDonald ( 2005 ) who successfully used different mass ratios of ethanol/water or methanol/water for production of nanoporous microparticles of hydrophobic compounds ( bendroflumethiazide and budesonide ) with and without ammonium carbonate. From the morphological characters of assorted p-aminosalicylic acid spray dried systems, it is obvious that the ethyl alcohol: H2O ratio employed is of import in the production of porous atoms.
It was seen that when the ethyl alcohol concentration was 70 % ( v/v ) , some of the atoms recovered were porous. When the dissolver concentration was increased to 80 % ( v/v ) , higher figure of spherical atoms was recovered, and the highest figure of porous atoms was obtained by utilizing 90 % ( v/v ) ethyl alcohol ( Chapters 3 ) . Using higher per centum of ethyl alcohol ( 95 % and 100 % ) resulted in spherical atoms with seeable holes. Solvent composing besides affected the cured atoms from spray drying of ammonium salt of p-aminosalicylic acid, where utilizing 90 % ethyl alcohol, atoms were more unvarying spherical atoms in comparing to the atoms obtained by spray drying from aqueous solution.Rabbani and Seville ( 2005 ) used a scope of ethanol/water co-solvent incorporating different concentrations of ethyl alcohol ( 10-50 % ( v/v ) ) to analyze the consequence of preparation constituents on the features of the end point spray dried pulverizations. The writers measured the viscousness of the preparations prior to spray drying. They reported that the viscousness was increased when the per centum of ethyl alcohol in the ethanol/water dissolver system was increased. The writers proposed that the alteration in viscousness of the solution being spray dried might impact the behavior of the solution at the spray drier nose, and therefore impact the size of the droplet produced, and accordingly, affect the morphology of the atoms produced.
In add-on to look intoing the consequence of altering the concentration of ethanol employed, the consequence of utilizing alternate dissolvers was besides examined. Methanol: H2O: ammonium carbonate was used as an alternate dissolver. As with the ethanolic systems, the H2O: methyl alcohol ratio employed was besides seen to be a cardinal parametric quantity when spray drying from methanolic solutions. For p-aminosalicylic acid/ammonium carbonate systems spray dried from 70 % ( v/v ) methyl alcohol, none of the atoms produced were porous.
For p-aminosalicylic acid/ammonium carbonate systems spray dried from 80 % and 90 % ( v/v ) methyl alcohol, spherical atoms were recovered ( Chapter 3 ) . Other research workers have besides reported correlativity between the co-solvent composing employed and the ability to bring forth porous atoms ( Tajber, 2005 ; McDonald, 2005 and Nolan, 2008 ) . Therefore, it can be concluded that the solvent composing is of cardinal importance in the production of porous atoms.The operational manner of the spray drying ( closed manner or unfastened manner ) affected the morphology of spray dried atoms.
The processing of a sample from the same spray drying conditions, entire solid concentration of 3 % , ammonium carbonate content of 20 % , inlet temperature of 78 & A ; deg ; C and utilizing 90 % ( v/v ) ethyl alcohol as dissolver utilizing both the unfastened and closed manner. Spray drying utilizing unfastened manner produced porous atoms and sums of microcrystalline atoms, on the other manus, spray drying utilizing closed manner constellation guerrilla shaped and spherical sums of atoms were produced as shown in Figure 6.2. Nolan ( 2008 ) reported that the spray drying manner had an consequence on the production of either NPMPs ( unfastened manner ) or non-porous atoms ( closed manner ) of sulfadimidine and sulfamerazine. McDonald ( 2005 ) besides studied the consequence of spray drying manner on production of NPMPs of bendroflumethiazide, he reported that porous atoms were recovered when unfastened manner was used while cured atom from spray drying utilizing closed manner were not porous. It should be noted that in the unfastened manner the drying gas is discharged after usage, on the other manus, in the closed manner the drying gas is continuously recycled.
Figure 6.2- SEM micrographs of 3 % ( w/v ) solution of PAS/ammonium carbonate systems spray-dried from 90 % v/v ethyl alcohol ( a ) unfastened manner ( B ) closed manner.McDonald ( 2005 ) reported that the differences in morphology when utilizing different runing manners possibly due to the fact that when runing in the closed manner the drying gas is recycled through the system so that although the dissolver is condensed, the drying gas may non be wholly dry of dissolver. When runing in the unfastened rhythm mode the drying gas exits the system on a continual footing drawing dissolver with it. McDonald ( 2005 ) anticipated that the gradient for vaporization and therefore the driving force may be greater in the unfastened manner, since the dissolver is traveling into a desiccant gas.The undermentioned hypothesis for formation of porous atoms of p-aminosalicylic acid from EtOH: ( H2O ) , based on the solubility of the compound and volatility of dissolvers, and ab initio proposed by Corrigan ( 2005 ) , Nolan ( 2008 ) based on experiments with several drug compounds.Spray drying of p-aminosalicylic acid from ethyl alcohol: H2O system involve readying of a solution of the drug ( p-aminosalicylic acid ) , which was later spray dried. The co-solvent system consisted of two dissolvers, with different boiling points ( boiling point of ethyl alcohol is 78 & A ; deg ; C, while it is 100 & A ; deg ; C for H2O ) .
p-aminosalicylic acid is more soluble in ethyl alcohol ( One gm dissolves in 21ml intoxicant, while 500 ml H2O required to fade out one gm of the drug ) , so ethanol is a good dissolver for the drug, while H2O is hapless solvent ( anti-solvent ) . This combination of co-solvents agencies that during the drying procedure the more volatile dissolver will vaporize foremost ( ethyl alcohol ) , with the solvent loss from these droplets ensuing in an addition in drug concentration in the less volatile dissolver ( H2O ) in which the drug is less soluble. Drying procedure will go on with continued solvent vaporization until the solvent content becomes excessively low to keep concentrated conditions at the droplet surface, so the drug solidifies out ab initio as liquid droplets.
Several liquid droplets are formed and by solvent vaporization, the drug droplets precipitate and come together and aggregate at the atom surface, taking to formation of sums of microcrystalline atoms and porous atom.The procedures of spray drying p-aminosalicylic acid with ammonium carbonate or ammonium hydrogen carbonate from ethanolic solutions involve readying of solution of p-aminosalicylic acid with ammonium carbonate or ammonium hydrogen carbonate. The undermentioned hypothesis for formation of porous atoms of p-aminosalicylic acid from EtOH: Water: ammonium carbonate or EtOH: Water: ammonium hydrogen carbonate, based on the solubility of p-aminosalicylic acid, physicochemical belongingss of ammonium carbonate and ammonium hydrogen carbonate and volatility of dissolvers. The more volatile dissolvers ( EtOH ) is better dissolvers for the p-aminosalicylic acid and the least volatile dissolver ( H2O ) is a hapless dissolver. During the atomization phase of the spray-drying procedure, droplets are formed incorporating the acid and the procedure additive in the solution. During drying of these droplets are exposed to the drying gas, and the procedure linear, ammonium carbonate or ammonium hydrogen carbonate, decompose to let go of ammonium hydroxide, the produced ammonium hydroxide may non vaporize wholly due to the acidic nature of p-aminosalicylic acid. At the same clip the more volatile dissolver ( EtOH with a boiling point of 78.
5 oC ) in which p-aminosalicylic acid is more soluble, may vaporize to a greater extent, ensuing in the droplet going richer in the less volatile dissolver constituent ( H2O with a boiling point of 100 oC ) , in which p-aminosalicylic acid is less soluble. The autumn in the solubility of the p-aminosalicylic acid may be dramatic and it may distill out ab initio as a nano-sized liquid within the droplet. As drying returns and farther dissolver loss occurs, p-aminosalicylic acid droplets become less unstable and come closer together, and may ensnare ammonium hydroxide ; the drug may precipitate out as primary nanoparticles and agglomerate together either at the atom surface or within the atom, taking to formation of microparticle.
As detailed throughout this thesis ammonium hydroxide was non wholly evaporated, taking to formation of a new solid province of the acidic drug compound with ammonium hydroxide. This was confirmed by elemental analysis, Karl Fischer titration, ammonia check and TGA.On the other manus, for hydrophilic compounds, the MeOH: BA dissolver system or the MeOH: Barium: H2O dissolver system was used to bring forth NPMPs, as shown in Chapter 5 the pick of these dissolvers based on the successful production of NPMPs of hydrophilic compounds trehalose by N & A ; iacute ; & A ; Oacute ; g & A ; aacute ; in ( 2006 ) and chitosan glutamate by Katheri ( 2007 ) utilizing these solvent systems. Spherical porous atoms were obtained on spray drying of PVP from 50:50 MeOH: BA. Spherical porous atoms of HP-b-CD were spray-dried from 1:6:6 and 1:15:15 Water: MeOH: BA.
Attempts to utilize similar dissolver systems to spray-dry INH were unsuccessful in footings of obtaining NPMPs ( utilizing either the MeOH: BA or the MeOH: Barium: H2O solvent systems ) .Sing the co-spray drying of drug/ excipients, in the current work different antitubercular drugs were co-spray dried with excipients as outlined in Table 6.4. By and large, two solvent systems, viz. MeOH: BA and H2O: MeOH: BA, were successfully used in this thesis to bring forth NPMPs of antitubercular drugs and excipients complexs as outlined in Table 6.
4. Depending on the per centum of excipient ( either HP-b-CD or PVP ) , different atom morphologies were produced. Spray drying of INH with 90 % PVP at inlet temperature of 100 & A ; deg ; C or 120 & A ; deg ; C resulted in formless solid provinces as confirmed by XRD.
The cured atoms were unvarying spherical NPMPs. Decreasing the proportion of PVP to 80 % of entire solid, produced spherical porous atoms merely when the recess temperature was 100 & A ; deg ; C. In contrast, mixtures of porous and non-porous atoms were recovered from spray drying of the same system at 120 & A ; deg ; C. This confirms the importance of recess temperature used in spray drying procedure.
It was besides observed that utilizing lower proportion of PVP ( 70 % and 50 % ) resulted in crystalline, smooth surfaces non-porous atoms as confirmed by XRD and SEM. These atoms were recovered from spray drying at 100 & A ; deg ; C or 120 & A ; deg ; C.Similarly, pyrazinamide was co-spray dried from methyl alcohol: butyl ethanoate with PVP representing 90 % , 80 % and 70 % by weight of solids. Different atom morphologies were produced based on the PVP contents, at higher proportion of PVP ( pyrazinamide/PVP 1:9 ) the spray-dried atoms were spherical porous atoms, while in lower proportions of PVP ( pyrazinamide/PVP 2:8 and 3:7 ) , the cured atoms were non-porous spherical with smooth surfaces and exposing concave depressions. It was observed that important alterations in atom form of spray-dried pyrazinamide or INH is dependent on the PVP proportion, which could be considered as a cardinal parametric quantity in readying of NPMPs of INH or pyrazinamide by spray drying.Isoniazid was spray dried with the excipient HP-b-CD at a concentration of 90 % , 80 % , 70 % and 50 % ( w/w ) , bring forthing an XRD formless and crystalline pulverizations depending on the concentration of HP-b-CD as shown in Chapter 5.
It was concluded that the concentration of HP-b-CD in the sample is an of import factor in readying of NPMPs of isoniazid/ HP-b-CD.Table 6.4 Compounds co-spray dried as NPMPs from different solvent provender systems in the present work, and mass ratio of NPMPs complexs.
|Compound||Feed system||Inlet temperature||Mass ratio ( complexs )|
|INH: HP-b-CD||Water: MeOH: Barium||100 & A ; deg ; C||1:9, 2:8|
|INH: PVP||MeOH: Barium||100 & A ; deg ; C||1:9, 2:8|
|INH: PVP||MeOH: Barium||120 & A ; deg ; C||1:9|
|pyrazinamide: PVP||MeOH: Barium||100 & A ; deg ; C||1:9|
6.5 spray drying of active pharmaceutical ingredient/excipient combinations
NPMPs are proposed to be peculiarly suited for pneumonic bringing and in peculiar dry pulverization inhalator preparation ( Tajber, 2005 ; Nolan, 2008 ) . As shown in Chapter 5, the production of porous atoms of INH and pyrazinamide required incorporation of high per centum of excipients. This will raise an of import inquiry about the feasibleness of disposal of these porous atoms.
It should be noted that several research workers studied the pharmacokinetics of inhaled antitubercular drugs and reported that disposal of antitubercular agents by inspiration decreases the needed dosage. Katiyar et al. , ( 2008 ) compared the unwritten versus pneumonic disposal of antitubercular agents. Briefly, a group of six healthy voluntaries aging from 20-50 received antitubercular drugs ( isoniazid 15 milligram, rifampicin 30 milligram and pyrazinamide 75mg with lactose as bearer ) utilizing dry pulverization inhalator, the atom size was 1-10 µm and mass average aerodynamic diameter of 2.79 µm.
Another group received unwritten tablets contain rifampicin 500mg, isoniazid 250 milligrams and pyrazinamide 1250 mg. the writers reported that the average concentrations of INH, pyrazinamide and rifampicin in epithelial liner fluid were 220, 15 and 83 times higher in inhaled group than those in the unwritten group. This confirms the decrease of dosage required for intervention of TB utilizing pneumonic delivered preparations.In add-on, NPMPs of spray dried antitubercular agents with excipients can be characterised by spherical form and little size which demonstrate superior aerosolisation public presentation in comparing to equivalent unrefined stuff, higher specific surface country values were besides obtained for NPMPs compared to micronised sample. Furthermore, in-vitro deposition informations showed the advantage of NPMPs of isoniazid/excipient produced over micronised INH in footings of respirable fraction ( Table 6.5 ) .Pharmacokinetic surveies of the spray dried preparations in this thesis were non made and this may be an country worth look intoing in future surveies of porous atoms of antitubercular drugs.
6 Aerosolisation public presentation of spray dried atoms
Bosquillon et al. , ( 2001 ) reported the importance of physical features, and their consequence on aerosolisation belongingss of inhaled atoms. Chapters 3 and 5 of this thesis discuss in item the physical belongingss ( atom size, denseness, surface country ) and in vitro drug deposition profile of different spray-dried systems of p-aminosalicylic acid, ammonium salt of p-aminosalicylic acid, INH and rifampicin. Physical belongingss and aerosolisation public presentation of these systems are compared in Table 6.5, to determine whether any general tendencies could be observed in these informations.By and large, The average atom size ( vitamin D ( 0.5 ) ) of the spray dried atoms, as determined from laser diffraction atom size analysis, was good within the optimal size-range for pneumonic drug bringing, that being between 1-5 ?m ( Bosquillon et al.
, 2004 ) . The smallest average atom size was 2.33±0.031 ?m for atoms of isoniazid/ HP-?-CD spray dried from H2O: MeOH: BA 1:15:15 at an inlet temperature of 100 & A ; deg ; C. The largest average atom size was 3.673±0.
00 ?m for ammonium salt of p-aminosalicylic acid spray dried from 90 % ethyl alcohol. The relationship between the average atom size ( vitamin D ( 0.5 ) ) of different spray-dried samples and the per centum of respirable fraction is shown in Figure 6.3.
It is obvious from the graph that there is no correlativity between the average atom size of the spray dried atoms and the respirable fraction of the pulverization atoms ( r2 = 0.201 ) . It should be noted that atoms recovered from spray drying of isoniazid/PVP 1:9 at 100 & A ; deg ; C, which exhibited the highest respirable fraction ( 46.3 % ) did non hold the smallest atom size. These consequences were compared favourably with the consequences reported by Nolan ( 2008 ) who showed that there was no correlativity between the average atom size and the respirable fraction of NPMPs of sulpha compounds, Na cromoglicate and sulpha or Na cromoglicate: PVP composites spray-dried systems.259
Chapter 6: General Discussion
5 Physical belongingss and in vitro aerosolisation public presentation of micronised stuffs and spray dried systems of p-aminosalicylic acid ( PAS ) , isoniazid ( INH ) and rifampicin ( RIF ) . * respirable fraction ( % ) as per NGI survey, all other consequences calculated from duplicate impinger surveies, SD= spray dried, HP-?-CD = Hydroxypropyl-?-cyclodextrin, PVP = polyvinyl pyrrolidone, vitamin D ( 0.5 ) = average atom size ( ?m ) as determined from laser diffraction atom size analysis.
|Atom sizevitamin D ( 0.5 ) ( ?m )||Respirable fraction ( % )||Surface country( m2/g )||Bulk denseness( g/cm3 )||Tapped denseness( g/cm3 )||Carr ‘s Index( % )|
|14.8±2.59||2.83 ± 0.21||0.230±0.
|6.19 ± 0.26||0.104±0.
|SD PAS /AC80:20||3.38±0.078||24.5±2.
|3.42 ± 0.32||0.122±0.003||0.167±0.008||26.8|
|SD PAS /AC 73:27||3.
|SD PAS salt||3.673±0.00||17.9±5.
|SD INH/ HP-?-CD 1:9||2.33±0.031||43.7±4.31||45.12± 0.29||0.115±0.
|SD INH/PVP 1:9 at 120 & A ; deg ; C||2.
|SD INH/PVP 2:8 at 100 & A ; deg ; C||2.
|SD INH/PVP 1:9 at 100 & A ; deg ; C||3.09±0.
|SD RIF composite from NAOH||3.12 ± 0.01||27.7 % ± 9.17*||2.30±0.
|SD RIF composite from AC||2.79 ± 0.01||41.8 % ± 6.5*||9.06±0.08||–||–|
259Chapter 6: General DiscussionFigure 6.3 consequence of average atom size ( d0.5 ) ( ?m ) on the respirable fraction ( % ) of different spray dried pulverizations. General Key: the trigon symbols represent rifampicin spray-dried systems, the square symbols represent spray-dried p-aminosalicylic acid systems and the round symbols represent spray-dried INH systems.Figure 6.4 show the relationship between Carr ‘s Index and the respirable fraction. There was no correlativity between the deliberate Carr ‘s Index and the respirable fraction of the spray dried pulverizations, with calculated R squared value of 0.077. These consequences are in understanding with the determination reported by Seville et al. , ( 2007 ) who reported that the Carr ‘s Index was non prognostic of aerosolisation public presentation of aminic acid-modified spray dried pulverizations. In another survey, Nolan ( 2008 ) studied the correlativity between the Carr ‘s Index and aerosolisation public presentation of spray dried sulfa compounds and Na cromoglicate, where there was no correlativity between the Carr ‘s Index and the respirable fraction, with r2 = 0.132.Figure 6.4 consequence of Carr ‘s Index ( per centum ) on the respirable fraction ( per centum ) of different spray dried pulverizations. General Key: the square symbols represent spray-dried p-aminosalicylic acid systems and the round symbols represent spray-dried INH systems.A weak correlativities was observed when plotting surface country against respirable fraction of different spray-dried samples ( r2 = 0.39 ) ( Figure 6.5 ) . The lowest surface country measurings were obtained for rifampicin composite prepared in Na hydrated oxide and spray-dried from aqueous solution, while this sample did non hold the lowest respirable fraction. It was besides observed that atoms recovered from spray drying of isoniazid/ HP-?-CD 1:9, which demonstrated the highest surface country ( 45.12 ( m2/g ) ) did non hold the highest respirable fraction.Figure 6.5 consequence of surface country ( m2/g ) on the respirable fraction ( per centum ) of different spray dried pulverizations. General Key: the square symbols represent spray-dried p-aminosalicylic acid systems and the round symbols represent spray-dried INH systems.6.7 Main findings from this thesis* Spray drying of p-aminosalicylic acid/ammonium carbonate did non ensue in production of the chief debasement merchandise of p-aminosalicylic acid ( 3-aminophenol ) . But a solid province was recovered, the stoichiometry of the cured atoms could be p-aminosalicylic acid: ammonium hydroxide: H2O 2:1:0.5, this was calculated from elemental analysis of the cured atoms and confirmed by Karl Fischer titration, ammonia check and TGA.* Spray drying of the acidic compounds without ammonium carbonate did non alter the chemical composing of the acidic compounds, nevertheless, spray drying with ammonium carbonate resulted in a new solid province, and the stoichiometry of cured atoms could be 2:1 acid: ammonium hydroxide. This was estimated from several elemental analyses of the spray dried samples.* The production of the new solid province upon spray drying of acidic compounds and ammonium carbonate depends on the interaction between the acidic compound and ammonium carbonate. The solid province of spray dried acidic compounds/ammonium carbonate was altered upon spray drying whenever the compound reacts with ammonium carbonate. Furthermore, in absence of such interaction, there was no change in solid province of co-spray dried acidic compound/ammonium carbonate.* Spray dried p-aminosalicylic acerb ammonium salt show good potency for pneumonic bringing as indicated by the addition in emitted dose relation to the micronised p-aminosalicylic acid.* Production of NPMPs of co-spray drying of INH: excipient ( PVP and HP- & A ; szlig ; -CD ) was dependent on the excipient contents, as high contents of the excipient was required to bring forth NPMPs. The cured atoms were XRD formless in high concentration of the excipient ( 80 % and 90 % ) , while, lower concentrations of the excipient ( 50 % ) gave preponderantly crystalline stage with extremums of the get downing INH.* Spray dried rifampicin composite have a greater disintegration rate than rifampicin unrefined stuff which can be attributed to the increased surface country and smaller atom size of the spray dried atoms.* This spray drying procedure can bring forth atoms suited for inspiration of p-aminosalicylic acid, INH and rifampicin.* Spray drying proved a successful method of bring forthing microspherical atoms which, displayed favorable atom features and in-vitro deposition, bespeaking good potency for pneumonic bringing, as indicated by the addition in emitted dose relation to micronised tantamount drug.* This type of new inspiration dry pulverization can be characterised by spherical porous atoms, these atoms have little size and big surface country. Therefore, they exhibit superior aerosolisation public presentation in comparing to micronised tantamount systems.6.8 Future work* Further survey is required to look into the benefits of utilizing ammonium salts of different acids, as a new technique for readying of porous atoms suited for inspiration.* Pharmacokinetic survey of the cured spray-dried atoms in comparing with the unrefined stuffs, and comparing between pneumonic, unwritten and endovenous path of disposal of the spray-dried atoms.* Further survey is required to look into the benefits of this spray drying procedure for the co-spray drying of drug-excipient atoms.* Further optimization of the other spray drying parametric quantities ( i.e. , pump rate, aspirator rate etc. ) for the production of NPMPs.259