the invention is directed to a pharmaceutical formulation comprising a pharmaceutically inert carrier and a therapeutically effective amount of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine wherein at least a portion of the 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine . however , prior to describing this invention in greater detail , the following terms will first be defined . it is to be understood that this invention is not limited to particular embodiments described , as such may , of course , vary . it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only , and is not intended to be limiting , since the scope of the present invention will be limited only by the appended claims . it must be noted that as used herein and in the appended claims , the singular forms “ a ”, “ an ”, and “ the ” include plural referents unless the context clearly dictates otherwise . thus , for example , reference to “ a pharmaceutically inert carrier ” includes a plurality of such carriers . unless defined otherwise , all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs . as used herein the following terms have the following meanings . as used herein , the term “ comprising ” or “ comprises ” is intended to mean that the compositions and methods include the recited elements , but not excluding others . “ consisting essentially of ” when used to define compositions and methods , shall mean excluding other elements of any essential significance to the combination for the stated purpose . thus , a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic ( s ) of the claimed invention . “ consisting of ” shall mean excluding more than trace elements of other ingredients and substantial method steps . embodiments defined by each of these transition terms are within the scope of this invention . the term “ about ” when used before a numerical designation , e . g ., temperature , time , amount , and concentration , including range , indicates approximations which may vary by (+) or (−) 10 %, 5 % or 1 %. as used herein , the term “ crystalline ” refers to solid 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine , wherein the solid exhibits long - range order in three dimensions of at least about 100 repeat units in each dimension . as used herein , the term “ non - crystalline ” refers to solid 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine , that does not exhibit any long range order in the positions of the atoms . thus , the term non - crystalline is intended to include not only solid which has essentially no order , but also solid which may have some small degree of order , but the order is in less than three dimensions and / or is only over short distances . non - crystalline compound may be characterized by techniques known in the art such as powder x - ray diffraction ( pxrd ) crystallography , solid state nmr , or thermal techniques such as differential scanning calorimetry ( dsc ). as used herein , the term “ solid dispersion ” refers to a dispersion in which at least a portion of the 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine , is non - crystalline and dispersed in a water soluble , biologically compatible polymer . the solid dispersions of the invention can be prepared by methods known in the art , including , but not limited to , solid dispersions formed by mechanical , thermal and solvent processes . exemplary mechanical processes include milling and extrusion ; melt processes , such as high temperature fusion , solvent - modified fusion and melt - congeal processes ; and solvent processes , such as non - solvent precipitation , spray coating and spray drying . see , for example , the following u . s . patents , the pertinent disclosures of which are incorporated herein by reference : u . s . pat . nos . 5 , 456 , 923 and 5 , 939 , 099 , which describe forming dispersions by extrusion processes ; u . s . pat . nos . 5 , 340 , 591 and 4 , 673 , 564 , which describe forming dispersions by milling processes ; and u . s . pat . nos . 5 , 707 , 646 and 4 , 894 , 235 , which describe forming dispersions by melt congeal processes . in one embodiment , the solid dispersion is formed by spray drying , as disclosed in european patent application publication no . 0 901 786 a2 . in this process , the 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine with or without the water soluble , biologically compatible polymer are dissolved in a suitable solvent , such as acetone , acetonitrile , methanol , ethanol , and methylethylketone , and the solvent is then rapidly removed from the solution by spray drying to form the solid dispersion . an example of a solid dispersion of this invention is the spray - dried solid dispersion comprising about 25 weight percent of compound a substantially homogenously intermixed with a water soluble , biologically compatible polymer . as used herein , the term “ pharmaceutically inert carrier ” refers to carriers which are inert , in the sense that they do not chemically react with 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine in an adverse manner , are pharmaceutically acceptable , and have at least some solubility in aqueous solution at physiologically relevant phs ( e . g . ph1 - 8 ). examples of pharmaceutically inert carriers are well known in the literature and , include by way of example only , cellulose acetate phthalate , magnesium stearate , lactose , lactose monohydrate , crospovidone , microcrystalline cellulose , colloidal silica dioxide , and the like . as used herein , the phrase “ water soluble , biologically compatible polymer ” refers to polymers which do not interact with 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine in an adverse manner that is detrimental to its use in vivo , are pharmaceutically acceptable , have at least some solubility in aqueous solution at physiologically relevant phs ( e . g . ph1 - 8 ) and which , when combined with compound a to form a solid dispersion as that term is defined above , impart enhanced solubility to compound a . the water soluble , biologically compatible polymer can be neutral or ionizable , and have an aqueous - solubility of at least 0 . 1 mg / ml over at least a portion of the ph range of 1 to 8 . in one embodiment , the glass - transition temperature ( tg ) of the polymer is great enough so that the resulting solid dispersion has a relatively high tg ( greater than 50 ° c . at 50 % relative humidity ( rh )). the polymer may have a tg of at least 100 ° c . at 50 % rh , at least 105 ° c . at 50 % rh , or even at least 110 ° c . at 50 % rh . as used herein , the term “ substantially homogeneous ” refers to solid dispersions as defined above wherein compound a is dispersed in the solid dispersion such that the concentration of compound a in any given amount of the solid dispersion is substantially uniform to that of any other given amount of the solid dispersion . as used herein , the phrase “ therapeutically effective amount ” means the amount of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine that will elicit the biological or medical response of a tissue , system , animal or human that is being sought by the attending clinician . “ a therapeutically effective amount ” includes the amount of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine that , when administered to a mammal for treating a disease , is sufficient to effect such treatment for the disease . the “ therapeutically effective amount ” will vary depending on the pharmaceutically inert carrier , the disease and its severity and the age , weight , etc ., of the mammal to be treated . this invention is predicated in part on the discovery that the water solubility and the bioavailability of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine is enhanced when at least a portion ( e . g ., more than 25 %) of the compound is non - crystalline and preferably employed in combination with a water soluble , biologically compatible polymer . without being limited to any theory , it is believed that the water soluble , biologically compatible polymer assists in maintaining the non - crystallinity of this compound . accordingly , the invention is directed to a pharmaceutical formulation comprising a pharmaceutically inert carrier , and a therapeutically effective amount of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine this invention is further directed to intermediates useful in this invention wherein said intermediate is a solid dispersion comprising a water soluble , biologically compatible polymer 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine wherein at least a portion of said 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine is non - crystalline . in one aspect provided is a pharmaceutical formulation comprising a pharmaceutically inert carrier and 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine wherein from about 25 % to about 100 %, by weight , of the 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine is non - crystalline and is contained within a solid dispersion which further comprises a water soluble , biologically compatible polymer . in some embodiments , from about 50 % to about 100 %, by weight , of the 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine is non - crystalline . in some embodiments , from about 75 % to about 100 %, by weight , of the 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine is non - crystalline . in some embodiments , about 95 %, by weight , of the 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine is non - crystalline . in some embodiments , the invention further comprises solid dispersions of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine substantially homogenously dispersed throughout the solid dispersion wherein the solid dispersion further comprises a water soluble , biologically compatible polymer . water soluble , biologically compatible polymers suitable for use in the pharmaceutical formulations of the present invention may be cellulosic or non - cellulosic . in certain embodiments , the polymers are neutral or ionizable in aqueous solution . of these , ionizable and cellulosic polymers are preferred , with ionizable cellulosic polymers being more preferred . exemplary water - soluble polymers include hydroxypropyl methyl cellulose acetate succinate , hydroxypropyl methyl cellulose , hydroxypropyl methyl cellulose phthalate , carboxy methyl ethyl cellulose , cellulose acetate phthalate , cellulose acetate trimellitate , and mixtures thereof . in some embodiments , said water soluble polymer is selected from the group consisting of povidone , copovidone , hypromellose acetate succinate , polyethylene glycol , hydroxypropyl methyl cellulose acetate succinate , hydroxypropyl methyl cellulose , hydroxypropyl methyl cellulose phthalate , carboxy methyl ethyl cellulose , cellulose acetate trimellitate and cellulose acetate phthalate . in some embodiments , said water soluble , biologically compatible polymer is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate , hydroxypropyl methyl cellulose , hydroxypropyl methyl cellulose phthalate , carboxy methyl ethyl cellulose , cellulose acetate trimellitate and cellulose acetate phthalate . in some embodiments , said polymer is cellulose acetate phthalate . in some embodiments , the solid dispersion comprises from about 5 % to about 75 %, by weight , of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine . in some embodiments , the solid dispersion is employed to provide for pharmaceutical formulations further comprising a pharmaceutically inert carrier wherein the formulation comprises from about 10 % to about 50 %, by weight , of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine . in some embodiments , the pharmaceutical formulation comprises from about 20 % to about 30 %, by weight , of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine . in some embodiments , the pharmaceutical formulation comprises about 5 %, by weight , of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine , or alternatively , about 10 % by weight , or about 15 % by weight , or about 20 % by weight , or about 25 % by weight , or about 30 % by weight , or about 35 % by weight , or about 40 % by weight , or about 45 % by weight , or about 50 % by weight , or about 55 % by weight , or about 60 % by weight , or about 65 % by weight , or about 70 % by weight , or about 75 % by weight , or about 80 % by weight , or about 85 % by weight , or about 90 % by weight , or about 95 % by weight . in some embodiments , the 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine can exist within the solid dispersion in relatively pure non - crystalline domains , or , in some embodiments , is distributed substantially homogeneously throughout the solid dispersion . in some embodiments , the solid dispersions of this invention are substantially homogenous and comprising a water soluble , biologically compatible polymer and a therapeutically effective amount of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine . in certain embodiments , the fraction of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine that is present in relatively pure non - crystalline domains or regions within the solid dispersion is relatively small , on the order of less than 20 % by weight , and preferably less than 10 % by weight of the total amount of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine in the composition . in one of its method aspects , the invention is directed to a method of producing solid dispersions comprising a therapeutically effective amount of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine and a water soluble , biologically compatible polymer , wherein from about 25 % to about 100 % by weight of the 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine is non - crystalline , which method comprises the steps of : in some embodiments , the non - crystalline form of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine can be prepared by combining crystalline 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine with a solvent to form solution c and rapidly removing solution c . the non - crystalline form of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine can then be used to form the solid dispersions described herein . in another of its method aspects , the present invention is directed to a method of producing solid dispersions wherein from about 25 % to about 100 % by weight of the 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine is non - crystalline , which method comprises the steps of : a ) combining non - crystalline 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine and a solvent to form solution a ; b ) combining solution a and a water soluble , biologically compatible polymer to form solution b ; and in some embodiments , the 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine step a ) is crystalline . however , in one embodiment , the non - crystalline form of this compound can be used . it is contemplated that any suitable water soluble , biologically compatible polymer can be used in step b ). non - limiting examples include , hydroxypropyl methyl cellulose acetate succinate , hydroxypropyl methyl cellulose , hydroxypropyl methyl cellulose phthalate , carboxy methyl ethyl cellulose , cellulose acetate phthalate , cellulose acetate trimellitate and cellulose acetate phthalate . in one embodiment , the water soluble , biologically compatible polymer is cellulose acetate phthalate . in some embodiments , the step of rapidly removing the solvent from solution b employs a spray - dryer . a spray dryer combines a liquid stream ( e . g ., solution a or b , above ) with a drying gas , and separates the solute or suspension as a solid and the solvent into a vapor . the solid can be collected in a drum or cyclone . the liquid input stream is sprayed through a nozzle into a hot vapor stream and vaporized . solids form as moisture quickly leaves the droplets . a nozzle is usually used to make the droplets as small as possible , maximising heat transfer and the rate of water vaporization . when a flammable solvent is used , oxygen is normally excluded from all parts of the spray drying apparatus . therefore , suitable drying gases for use in the methods disclosed herein include inert gases , such as nitrogen , argon , carbon dioxide , helium , krypton , and xenon , at a flow rate of about 1200 g / min to about 2500 g / min . in some embodiments , the flow rate is about 1850 g / min . typical droplet sizes can range from about 1 to about 500 micrometers , depending on the nozzle selected . accordingly , in some embodiments , the smallest diameter of the solid dispersion is from about 1 to about 500 micrometers , or from about 1 to about 400 micrometers , or from about 5 to about 300 micrometers , or from about 5 to about 200 micrometers , or from about or 5 to about 100 micrometers , or from about or 5 to about 80 micrometers , or from about or 5 to about 60 micrometers , or from about or 5 to about 40 micrometers , or from about or 5 to about 50 micrometers , or from about or 10 to about 40 micrometers , or from about or 15 to about 35 micrometers , or about 25 micrometers . in some embodiments , solution b is delivered to the spray - dryer at a rate of from about 175 grams / min to about 250 g / min . in some embodiments , solution b is delivered to the spray - dryer at a rate of from about 200 grams / min to about 230 g / min . in some embodiments , solution b is delivered to the spray - dryer at a pressure of from about 150 psi to about 500 psi . in some embodiments , solution b is delivered to the spray - dryer at a pressure of from about 200 psi to about 450 psi . in some embodiments , solution b is delivered to the spray - dryer at a pressure of from about 300 psi to about 315 psi . for commercial scale manufacturing , the drying gas flow rate can be significantly higher . the above provides for rapid removal of the solvent such that at least a portion of compound a remains non - crystalline . suitable solvents for use in the spray - dryer include polar organic solvents , such as alcohols such as methanol , ethanol , n - propanol , isopropanol , and butanol ; ketones such as acetone , methyl ethyl ketone and methyl isobutyl ketone ; esters such as ethyl acetate and propyl acetate ; and various other solvents , such as tetrahydrofuran , acetonitrile , methylene chloride , toluene , and 1 , 1 , 1 - trichloroethane . in some embodiments , the solvent of solution a is acetone . the temperature of the spray - dryer can be adjusted based on the solvent employed and the size of the nozzle . in some embodiments , the spray drying is performed at a temperature of between about 100 ° c . and about 150 ° c . in some embodiments , the spray drying is performed at a temperature of between about 115 ° c . and about 135 ° c . in some embodiments , the spray drying is performed at a temperature of about 125 ° c . in some embodiments , the solid dispersions of this invention can be prepared by hot melting the water - soluble , biologically compatible polymer , adding the desired amount of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine to the hot melt under conditions to provide a uniform dispersion of the hot melt and then extruding the hot melt to form a solid dispersionsolid dispersion . the solid dispersion produced herein is sometimes referred to as a “ hot melt extrudate ”. suitable polymers for hot melt purposes include , for example , povidone , copovidone , hypromellose acetate succinate , and polyethylene glycol . the pharmaceutical formulations of the present invention comprise a therapeutically effective amount of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine , collectively referred to herein a “ compound a ”. methods for the preparation of the compound a are disclosed in u . s . ser . no . 61 / 351 , 803 filed on jun . 4 , 2010 which application is incorporated in its entirety by reference . exemplary methods for the preparation of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine for use in the pharmaceutical formulations disclosed herein are detailed herein below . ( a ) contacting a compound of formula ( i ) with di - tert - butyl dicarbonate ( boc 2 o ) to form a compound of formula ( ii ) ( b ) contacting the compound of formula ( ii ) with a compound of formula ( iii ) to form a compound of formula ( iv ) ( c ) contacting the compound of formula ( iv ) with a compound of formula ( v ) to form a compound of formula ( vi ) ( d ) contacting the compound of formula ( vi ) with a compound of formula ( vii ) to form a compound of formula ( viii ) ( e ) contacting the compound of formula ( viii ) with acid to form a compound of formula ( ix ) ( f ) contacting in dimethylformamide in presence of base the compound of formula ( ix ) with a compound of formula ( x ) wherein l is a leaving group such as f , cl , br , i , os ( o ) 2 cf 3 , os ( o ) 2 ch 3 and os ( o ) cf 3 comprising contacting a compound of formula ( xxiv ) with a compound of formula ( vii ) in presence of base , such as naoh , na 2 co 3 , k 2 co 3 , cs 2 co 3 and nah ( a ) contacting a compound of formula ( i ) with a compound of formula ( xxi ) wherein t is a leaving group such as f , cl , br , i , os ( o ) 2 cf 3 , os ( o ) 2 ch 3 and os ( o ) cf 3 to form a compound of formula ( xxii ) ( b ) contacting the compound of formula ( xxii ) with a compound of formula ( iii ) to form a compound of formula ( xxiii ) ( c ) contacting the compound of formula ( xxiii ) with a compound of formula ( v ) to form a compound of formula ( xxiv ) ( a ) contacting a compound of formula ( iv ) with acid to form a compound of formula ( xi ) ( b ) contacting a compound of formula ( xxi ) wherein t is a leaving group such as f , cl , br , i , os ( o ) 2 cf 3 , os ( o ) 2 ch 3 and os ( o ) cf 3 , to form a compound of formula ( xxiii ) ( c ) contacting the compound of formula ( xxiii ) with a compound of formula ( v ) to form a compound of formula ( xxiv ) in some aspects , the compound of formula ( ix ) and ( x ) are contacted at a temperature of 60 ° c . to 100 ° c . in other aspects , the temperature is 70 ° c . to 90 ° c ., 79 ° c . to 81 ° c ., or 80 ° c . in some aspects , the base is naoh , na 2 co 3 , nahco 3 , khco 3 , k 2 co 3 , cs 2 co 3 , et 3 n ( triethylamine ) and i - pr 2 net ( diisopropylethylamine ). in some embodiments , the compound of formula ( ix ) is prepared by contacting a compound of formula ( viii ) with acid in some embodiments , the compound of formula ( viii ) is prepared by contacting a compound of formula ( vi ) with a compound of formula ( vii ) in some aspects , the compound of the compounds of formula ( vi ) and formula ( vii ) are contacted in a polar organic solvent selected from dimethyl formamide ( dmf ) and acetonitrile ( mecn ) and in presence of base . in some aspects , the base is selected from the group consisting of naoh , na 2 co 3 , k 2 co 3 , cs 2 co 3 and nah . in some aspects , the compound of the solvent is mecn . in other aspects , the solvent is dmf . in some aspects , the base is cs 2 co 3 . in still other aspects the base is k 2 co 3 . in some embodiments , the compound of formula ( vi ) is prepared by contacting a compound of formula ( iv ) with a compound of formula ( v ) in some aspects , the compounds of formula ( iv ) and formula ( v ) are refluxed in a polar organic solvent in presence of base . in some such aspects , the base is selected from the group consisting of na 2 co 3 , k 2 co 3 , cs 2 co and mgco 3 . in some embodiments , the compound of formula ( vii ) is prepared by contacting 4 - aminophenol with sodium azide and trimethylorthoformate . in some embodiments , the compound of formula ( iv ) is prepared by contacting a compound of formula ( ii ) with a compound of formula ( iii ) in some embodiments , the compound of formula ( ii ) is prepared by contacting a compound of formula ( i ) with di - tert - butyl dicarbonate ( boc 2 o ). ( a ) contacting the compound of formula ( xxiii ) with a compound of formula ( xxiv ) to form a compound of formula ( xxv ) ( b ) contacting the compound of formula ( xxv ) with a reducing agent , for example lithium aluminum hydride ( lialh 4 ), lithium borohydride ( libh 4 ), or diisobutyl aluminum hydride ( dibal ) to form a compound of formula ( xxvi ) ( a ) contacting the compound of formula ( xxiii ) with a compound of formula ( xxiv ) to form a compound of formula ( xxv ) ( b ) contacting the compound of formula ( xxv ) with a reducing agent to form a compound of formula ( xxvi ) ( c ) converting the compound of formula ( xxvi ) to a compound of formula ( xxvii ) wherein q is a leaving group such as cl , br , i , os ( o ) 2 cf 3 , os ( o ) 2 ch 3 and os ( o ) cf 3 comprising contacting a compound of formula ( xxvii ) wherein q is a leaving group such as cl , br , i , os ( o ) 2 cf 3 , os ( o ) 2 ch 3 and os ( o ) cf 3 with a compound of formula ( vii ) in presence of base , for example naoh , na 2 co 3 , k 2 co 3 , cs 2 co 3 and nah . in some aspects provided is an intermediate compound for use in the preparation of 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine selected from the group consisting of wherein q is a leaving group such as cl , br , i , os ( o ) 2 cf 3 , os ( o ) 2 ch 3 and os ( o ) cf 3 . in other embodiments , provided is 5 - ethyl - 2 -{ 4 -[ 4 -( 4 - tetrazol - 1 - yl - phenoxymethyl )- thiazol - 2 - yl ]- piperidin - 1 - yl }- pyrimidine having carbon 14 isotope labeling about the carbon atoms in the phenyl ring . the labeled compound can be prepared according to the following scheme from commercially available 14c ( u )]- 4 - aminophenol hydrochloride ( archemi 1 - 800 - 331 - 6661 , arc - 545 ): in accordance with the present invention methods of treating a disease or condition selected from the group consisting of type i diabetes , type ii diabetes and metabolic syndrome are provided . the method comprises administering to a subject in need of such treatment an effective amount of a pharmaceutical formulation of the present invention . in another aspect , methods of raising intracellular levels of ca 2 + in a cell expressing gpr119 are provided . the method comprises exposing a cell that expresses gpr119 to a pharmaceutical formulation of the invention . ca 2 + levels can be determined by methods known in the art . in one embodiment , the cell that expresses gpr119 is a pancreatic cell , an islet cell , or a beta cell , an intestinal endocrine cell , an l cell or a k cell . another aspect of the invention provides a method of stimulating insulin production in a mammal , in particular a human . the method comprises administering an effective amount of a pharmaceutical formulation of the invention to the mammal . in response to administration of a compound to the subject , insulin is produced by the beta cells . methods by which a skilled artisan can measure insulin secretion in laboratory animals in response to administration of a pharmaceutical formulation of the invention are known in the art . in another aspect , the invention provides a method of stimulating insulin secretion in a mammal , in particular a human . the method comprises administering an effective amount of a pharmaceutical formulation of the invention to the mammal . in response to administration of a pharmaceutical formulation to the subject , insulin is secreted into the blood stream by the beta cells . a further aspect of the invention provides a method of stimulating glucose - dependent insulin secretion in a mammal , in particular a human . the method comprises administering an effective amount of a pharmaceutical formulation of the invention to the mammal . after administration to the subject , insulin is secreted into the blood stream by the beta cells in a glucose - dependent manner . methods that show the blood glucose lowering effects of the pharmaceutical formulations of the invention are known in the art . in another embodiment , the invention provides methods of lowering blood glucose in a mammal , preferably a human . the method comprises administering an effective amount of a pharmaceutical formulation of the invention to the mammal . in response to administration of a pharmaceutical formulation to the subject , blood glucose levels are lowered . in one embodiment , the blood glucose in a mammal is reduced by about 5 % or more , or about 15 % or more , or about 25 % or more , or about 35 % or more , or about 45 % or more , or about 50 % or more , or about 60 % or more , or about 70 % or more , or about 75 % or more , or about 80 % or more , or about 85 % or more , or about 90 % or more . in some embodiments , the method further comprises steps to measure blood glucose levels before and after administration of a pharmaceutical formulation of the invention . blood glucose levels are easily measured by numerous commercially available glucose monitoring devices that measure blood glucose from samples of blood or urine . blood glucose can also be measured by commercially available glucometers that do not require blood or urine samples . methods that teach how to measure improvements in diabetes parameters , including blood glucose monitoring are known in the art . another aspect of the invention provides a method of stimulating incretin production in a mammal , in particular a human . the method comprises administering an effective amount of a pharmaceutical formulation of the invention to the mammal . in response to administration of a pharmaceutical formulation to the subject , glucagon - like peptide 1 and glucose - dependent insulinotropic polypeptide is produced by the intestinal endocrine cells . methods by which a skilled artisan can measure incretin production in laboratory animals in response to administration of a pharmaceutical formulation of the invention are known in the art . the present invention will be described in further detail by the following examples . it is to be understood , however , that these examples are given for illustrative purpose only and are not construed to limit the scope of the present invention . the present invention will be described in further detail by the following examples . it is to be understood , however , that these examples are given for illustrative purpose only and are not construed to limit the scope of the present invention . to a suspension of iosnipecotamide ( 255 g , 1 . 99 mol ) and 4 - dimethylamino - pyridine ( 204 mg , 1 . 82 mol ) in methylene chloride ( 1500 ml ) in a 5 - lite of three - neck flask was added a solution of di - tert - butyl dicarbonate ( 502 g , 2 . 30 mol , 1 . 15 eq .) in methylene chloride ( 500 ml ) dropwise at room temperature with mechanic stirring . a clear solution was reached at the end of the adding . after stirring at room temperature for two more hours , the solution was washed with phosphoric acid water solution ( 2 . 5 v / v %, 500 ml ), water ( 500 ml ), half saturated sodium bicarbonate water solution ( 500 ml ), and 10 % of brine ( 500 ml ). the organic phase was dried over anhydrous sodium sulfate . during the course of removing of the methylene chloride , ethyl acetate ( 100 ml ) and heptane ( 200 ml ) was added . after removing the methylene chloride , the white solid formed was filtrated , washed with hexane , and dried to give 414 g ( 95 %) of product . to a suspension of 4 - carbamoyl - piperidine - 1 - carboxylic acid tert - butyl ester ( 288 g , 1 . 26 mol ) in dimethoxyethane ( 2000 ml ) and methylene chloride ( 800 ml ) in a 5 - lite of three - neck flask was added lawesson &# 39 ; s reagent ( 255 g , 0 . 63 mol ). the mixture was stirred at room temperature for 80 min . tlc check there was no starting material left . the solvents were removed under vacuum . the residue was dissolved in ethyl acetate ( 1500 ml ), and washed with half saturated potassium carbonate water solution ( 500 ml each , two times ), 50 % of brine ( 500 ml ). the organic phase was dried over anhydrous sodium sulfate and concentrated to dry . the obtained solid was dissolved in ethyl acetate ( 1000 ml ) and filtered at hot to remove insoluble white stuff . to the solution was added heptane ( 300 ml ). after removing most of ethyl acetate , the solid formed was filtrated , washed with hexane - ether ( 1 : 1 ), and dried to give 252 g ( 82 %) of product . tlc : dichloromethane - methanol 90 : 10 , rf ( product )= 0 . 37 , uv and iodine positive ; rf ( starting material )= 0 . 28 , iodine positive . to a 2 - liter one - neck flask under air , immersed in an oil bath and fitted with a refluxing condenser , was added 4 - aminophenol ( 50 g , 0 . 459 mol ), acetic acid ( 500 ml ), sodium azide ( 41 . 7 g , 0 . 642 mol ), and trimethyl orthoformate ( 70 ml , 68 g , 0 . 642 mol ). the mixture was stirred at 60 ° c . ( oil bath ) for one hour and then refluxed ( oil bath , 100 ° c .) for 3 hours . a clear solution was formed during the refluxing . the temperature of solution was lowered to 80 ° c . ( oil bath ) and water ( 300 ml ) was added slowly . the temperature of the solution was cooled down to room temperature . the solid formed over night was filtered and dried to give 61 . 7 g ( 83 %) of product as first crop . tlc : hexane - ethyl acetate 50 : 50 , rf ( product )= 0 . 28 ; rf ( starting material )= 0 . 23 , uv and iodine positive . 1 hnmr ( 400 mhz , d 3 cod ), δ 9 . 58 ( s , 1h ), 7 . 61 ( d , j = 9 . 0 hz , 2h ), 6 . 97 ( d , j = 9 . 0 hz , 2h ) ppm . modified procedure : the reactions were carried out at 1 . 5 times of the abovementioned scale . a 2 - liter flask under air was charged with acidic acid followed by 4 - aminophenol , sodium azide , and trimethyl orthoformate with stirring at room temperature . the flask was fitted with a bump trap and was heated to 100 ° c . ( oil bath ) during the course of 1 to 1 . 5 hours . solid started to precipitate and the temperature of mixture was lowered to 80 ° c . water was added and the mixture was cooled down to room temperature . the mixture was filtered and the solid was washed with water and dried to give the desired product (& gt ; 88 % yield ). 1 hnm ( 400 mhz , d 3 cod ), δ 9 . 58 ( s , 1h ), 7 . 61 ( d , j = 9 . 0 hz , 2h ), 6 . 97 ( d , j = 9 . 0 hz , 2h ) ppm . to a 500 ml flask under air , immersed in an oil bath and a condenser , was added 4 - thiocarbamoyl - piperidine - 1 - carboxylic acid tert - butyl ester ( 29 g , 120 mmol ), acetone ( 300 ml ) mgso 4 ( 21 . 6 g , 180 mmol ) and mgco 3 ( 10 g , 120 mmol ), 1 , 3 - dichloroacetone ( 19 . 8 g , 156 mmol ). the resulting mixture was heated under reflux overnight , cooled and filtered through celite . the solvent was removed in vacuo and the residue was redissolved with etoac ( 500 ml ). the resulting solution was washed successively with 5 % nahso 3 ( twice ), saturated nahco 3 and brine . after drying ( naso 4 ), the solvent was removed to afford 35 g of the title compound as light yellow oil . the oil became dark solid after standing at room temperature . the color could be removed by activated charcoal . the purity was improved from 92 % to 96 %. 1 h nmr ( cdcl 3 ): δ 7 . 20 ( 1h , s ), 4 . 67 ( 2h , s ), 4 . 20 ( 2h , br ), 3 . 16 ( 1h , m ), 2 . 87 ( 2h , m ), 2 . 09 ( 2h , m ), 1 . 72 ( 2h , m ), 1 . 47 ( 9h , s ). a mixture of 4 -( 4 - chloromethyl - thiazol - 2 - yl )- piperidine - 1 - carboxylic acid tert - butyl ester ( 35 g , 0 . 11 mol ), 4 - tetrazol - 1 - yl - phenol ( 21 . 4 g , 0 . 132 mol ), cs 2 co 3 ( 43 g , 0 . 132 mol ), ki ( 1 . 8 g , 11 mmol ) in acetonitrile ( 400 ml ) was heated under reflux overnight . after cooling , the solid was filtered through a pad of celite . the filtrate was concentrated in vacuo . the residue was dissolved in methylene chloride and washed with 5 % aqueous naoh ( 3 times ), water and brine . after drying ( naso 4 ), the solvent was removed . the resulting solid was dissolved in ethyl acetate . the resulting solution was heated with activated charcoal and filtrated through a pad of celite . the filtrate was concentrated and the residue was purified by recrystallization from etoac / hexane to afford 37 g desired product . 1 h nmr ( cdcl 3 ): δ 8 . 01 ( 1h , s ), 7 . 61 ( 2h , d , j = 8 . 8 hz ), 7 . 25 ( 1h , s ), 7 . 15 ( 2h , d , j = 8 . 8 hz ), 5 . 22 ( 2h , s ), 4 . 2 ( 2h , br ), 3 . 17 ( 1h , m ), 2 . 87 ( 2h , m ), 2 . 11 ( 2h , m ), 1 . 73 ( 2h , m ), 1 . 46 ( 9h , s ). to a 3 - l 3 - neck flask under n 2 fitted with an addition funnel , was added 400 ml of anhydrous methylene chloride ( j . t . baker low water grade ; the ch 2 cl 2 will facilitate the solubility of substrate ) and 115 . 59 g of t - butyl carbamate substrate ( 0 . 26 mol ) in one - portion . after stirring at rt for 2 ˜ 5 minutes , to the resulting almost clear solution was added 400 ml of methanol ( j . t . baker hplc grade ). the resulting clear brown solution was cooled to 0 - 4 ° c . ( ice - water bath temperature ) with stirring , and then 330 ml of 4n hcl in 1 , 4 - dioxane ( 1 . 32 mol , 5 eq .) was added dropwise over 30 minutes . the ice - water bath was removed , and the resulting brown homogeneous solution was stirred at rt overnight ( 15 hours ). at least 7 hours is needed to bring the reaction to completion . the reaction mixture was aliquoted and quenched into 2n naoh , and then extracted w / etoac . 1 h nmr in dmso - d 6 . diagnostic peaks : free - amine product δ 7 . 63 ( s , 1h ); starting material ( substrate ) δ 7 . 66 ( s , 1h ). typically , the conversion was estimated via the integral of the italicized signals : 4 hrs , 80 % conversion ; 6 hrs , 95 % conversion . the reaction solution was allowed to cool to 10 ° c . ( ice - water bath temp ), and then a solution of 15 % ( w / v ) naoh ( 705 ml ; 2 . 64 mol , 2 eq . of hcl used ) in ˜ 500 ml of water was added dropwise over 15 minutes . ( diluted 15 % aq . naoh was used to ensure no precipitation ( inorganic salt ) in the organic phase ). immediate phase break was observed when the stirring was stopped to give a brown aqueous layer on top and a pale yellow organic layer on the bottom . the organic layer was collected , and the remaining aqueous layer was extracted with ch 2 cl 2 ( 500 ml × 2 ). the organic layers were combined , rinsed with ˜ 500 ml of water , and dried over anhy . na 2 so 4 . after most of solvents were removed in vacuo , precipitation began . to this pale yellow mixture was added 500 ml of heptane to give a pale yellow slurry . the resulting precipitate was collected on a filter funnel , and the mother liquor was stripped down . the combined solids were rinsed with heptane ( 200 ml ). after air - drying overnight , 84 . 1 g ( 94 % yield ) of free amine was obtained as a white or an off - white solid . 1 h nmr ( dmso - d 6 ): δ 9 . 98 ( 1h , s ), 7 . 80 ( 2h , d , j = 8 . 0 hz ), 7 . 63 ( 1h , s ), 7 . 28 ( 2h , d , j = 8 . 0 hz ), 5 . 20 ( 2h , s ), 3 . 05 ( 1h , m ), 2 . 97 ( 2h , m ), 2 . 56 ( 2h , m ), 1 . 93 ( 2h , m ), 1 . 55 ( 2h , m ) ppm . instead of using hcl , if the reaction was treated with 5 eq . tfa in ch 2 cl 2 at rt , ˜ 50 % of an unknown by - product will be generated which can be seen by taking a 1 h nmr in dmso - d 6 : diagnostic peaks δ 7 . 45 ( 1h , s ), 6 . 61 ( 2h , d , j = 8 . 8 hz ), 6 . 44 ( 2h , d , j = 8 . 8 hz ), 4 . 89 ( 2h , s ) ppm . the use of ch 2 cl 2 / ch 3 oh as co - solvents will eliminate the formation of impurities seen with other solvents . the use of 1 , 4 - dioxane , 1 , 4 - dioxane / methanol , or methylene chloride will produce a tiny amount of detectable impurity which can be seen by 1 h nmr in dmso - d 6 : diagnostic peaks δ 6 . 82 ( m ), 6 . 56 ( m ), 4 . 99 ( m ) ppm . this impurity will be carried over to the final product in the next step , and cannot be removed by purification via recrystallization . to a 3 - l 3 - neck flask under n 2 was added 105 . 7 g of crude free amine ( 0 . 31 mol ), 88 . 0 g of 2 - chloro - 5 - ethylpyrimidine ( 0 . 62 mol , 2 eq .) in one - portion , and then 800 ml of anhydrous dmf . after stirring at rt for 1 ˜ 2 minutes , to the resulting clear solution was added 64 . 0 g of anhy . k 2 co 3 ( 0 . 46 mol , 1 . 5 eq .) in one - portion . the flask was immersed in a pre - heated oil bath ( 90 ° c ., oil - bath temperature ), and the reaction mixture was stirred at 90 ° c . ( oil - bath temperature ) for 3 . 5 hours . the reaction mixture was aliquoted and quenched into water / brine , and then extracted w / etoac . 1 h nmr in dmso - d 6 . diagnostic peaks : product δ 7 . 66 ( s , 1h ); free - amine ( starting material ) δ 7 . 63 ( s , 1h ); pyrimidine δ 8 . 67 ( s , 2h ), dmf δ 7 . 03 ( s , 1h ). typically , the conversion was estimated via the integral of the italicized signals . complete conversion was observed between 3 to 4 hours . prolonged heating (& gt ; 5 hours ) resulted in the formation of the unidentified impurity . the reaction mixture was transferred to a 5 - l 3 - neck flask , and allowed to cool with stirring to rt with ice - water bath . to the reaction mixture at rt under stirring vigorously ( mechanical stirrer ) and approximate 2000 ml of water was added slowly dropwise over 30 minutes to give an off - white slurry ( precipitation began when ˜ 500 ml of water was added ). after the addition was finished , the resulting slurry was stirred at rt for an additional 10 ˜ 15 minutes . the off - white precipitate was filtered and then rinsed with water ( 250 ml × 2 ). after air - drying overnight , approximate 387 g of wet off - white solid was obtained , and redissolved in 1500 ml of etoac by heating at 55 ° c . ( internal solution temperature ) for ca . 10 minutes . the resulting pale - yellow solution was washed with water ( 250 ml × 3 ) and water / brine ( 200 ml / 100 ml ), and dried over anhy . na 2 so 4 . after most of solvents were removed in vacuo , precipitation began and then gave an off - white slurry (˜ 500 ml of solvents left ). the resulting white precipitate was collected on a filter funnel , and rinsed with etoac ( 300 ml × 2 ). the mother liquor was kept to do another recrystallization later on , and the precipitate on the filter funnel was rinsed once more time with 300 ml of heptane . after air - drying , 91 . 11 g of product was obtained as a white solid . the mother liquor ( without heptane ) was stripped down in vacuo until a thick slurry was formed , and the resulting precipitate was filtered and rinsed twice with etoac ( 100 ml × 2 ) and once with heptane ( 100 ml ) to give another 16 . 84 of product as a white solid . overall yield 78 %. 1 h nmr ( dmso - d 6 ): δ 9 . 98 ( 1h , s ), 8 . 24 ( 2h , s ), 7 . 80 ( 2h , d , j = 6 . 8 hz ), 7 . 66 ( 1h , s ), 7 . 28 ( 2h , d , j = 6 . 8 hz ), 5 . 20 ( 2h , s ), 4 . 67 ( 2h , m ), 3 . 32 ( 1h , m ), 3 . 01 ( 2h , m ), 2 . 43 ( 2h , q , j = 7 . 2 hz ), 2 . 07 ( 2h , m ), 1 . 59 ( 2h , m ), 1 . 11 ( 3h , t , j = 7 . 2 hz ) ppm . all the remaining mother liquors were combined , and concentrated in vacuo to give 15 . 07 g of an off - white solid which would be purified by one more time recrystallization with etoac or chromatography with 70 % etoac / hexanes on silica gel . this reaction was also tried at a small scale ( 0 . 6 mmol ) at higher concentrations ( 0 . 6 m with 2 eq . of pyrimidine and 1 . 2 m with 1 . 3 eq . of pyrimidine ). free amine ( 207 mg , 0 . 60 mmol ) was treated at 90 ° c . with 178 . 3 mg of 2 - chloro - 5 - ethylpyrimidine ( 2 eq .) and anhy . k 2 co 3 ( 1 . 5 eq .) in 1 ml of dmf ( the final concentration of the free amine is ˜ 0 . 60 m ). the reaction was complete in 2 hours . however , the reaction mixture was not homogenous at the end because of the precipitation of product . free amine ( 212 mg , 0 . 62 mmol ) was treated at 90 ° c . with 114 . 2 mg of 2 - chloro - 5 - ethylpyrimidine ( 1 . 3 eq .) and anhy . k 2 co 3 ( 1 . 5 eq .) in 0 . 5 ml of dmf ( the final concentration of the free amine is ˜ 1 . 2 m ). the reaction was achieved ˜ 85 % conversion in 2 hours , and the reaction mixture was not homogenous because of the precipitation of product . significant amount of the unidentified by - products were formed after heating at 90 ° c . for 4 hours . to a kimax tube ( 25 × 150 mm ) were added 4 - aminophenol ( 200 mg , 1 . 83 mmol ), sodium azide ( 167 mg , 2 . 57 mg , 1 . 4 eq . ), acetic acid ( 1 ml ), 2 drops of concentrated hydrochloride acid , and trimethyl orthoformate ( 0 . 5 ml ) at room temperature . the mixture was stirred , and heated up to 100 ° c . on a heating block . after at 100 ° c . for 20 min , the temperature was lowered to 80 ° c ., and water ( 1 ml ) was added . when the mixture was cooled down to room temperature , the liquids were removed using pipette . the solid was washed with water ( 1 ml × 3 ) and heptane ( 1 ml ), and tried under vacuum . the white solid was used in the next step without further purification . tlc : hexane - ethyl acetate 50 : 50 , rf ( product )= 0 . 28 ; rf ( starting material )= 0 . 23 , uv and iodine positive . 1 hnmr ( 400 mhz , d 3 cod ), δ 9 . 58 ( s , 1h ), 7 . 61 ( d , j = 9 . 0 hz , 2h ), 6 . 97 ( d , j = 9 . 0 hz , 2h ) ppm . to the same tube from above reaction ( with the synthesized 4 - tetrazol - 1 - yl - phenol in ) were added 2 -[ 4 -( 4 - chloromethyl - thiazol - 2 - yl )- piperidin - 1 - yl ]- 5 - ethyl - pyrimidine ( 571 - 110 , 532 mg , 1 . 65 mmol ), cs 2 co 3 ( 596 mg , 1 . 83 mmol ), ki ( 14 mg ) in acetonitrile ( 2 ml ). the mixture was heated at 60 ° c . for 10 hours ( the reaction was followed by hplc / ms ). after cooling the reaction mixture was treated with ethyl acetate ( 100 ml ) and water ( 20 ml ). the water phase was separated out . the organic phase was washed with brine ( 20 ml ), dried over anhydrous sodium sulfate , concentrated . the residue was dissolved in small amount of dichloromethane and purified by 40 g silica gel combiflash column to afford 580 mg ( 70 % yield in two steps ) of desired product as white solid . 1 h nmr ( dmso - d 6 ): δ 9 . 98 ( 1h , s ), 8 . 24 ( 2h , s ), 7 . 80 ( 2h , d , j = 6 . 8 hz ), 7 . 66 ( 1h , s ), 7 . 28 ( 2h , d , j = 6 . 8 hz ), 5 . 20 ( 2h , s ), 4 . 67 ( 2h , m ), 3 . 32 ( 1h , m ), 3 . 01 ( 2h , m ), 2 . 43 ( 2h , q , j = 7 . 2 hz ), 2 . 07 ( 2h , m ), 1 . 59 ( 2h , m ), 1 . 11 ( 3h , t , j = 7 . 2 hz ) ppm . ms ( esi ), m / z 449 . solid dispersion formulations were prepared using the leistritz 16 - mm extruder , examining the effect of polymer type , drug loading and processing temperature on the critical product attributes of compound a solid dispersions . exemplifying process conditions and formulation variables are presented in table 1 . solid dispersion formulations of compound a in eudragit ® e po ( formulation 2 ) and kollidon ® va 64 ( formulation 3 ) were examined for dissolution behavior under non - sink conditions to assess oral bioavailability enhancement . studies were conducted in three different media preparations , including : simulated gastric fluid , fed state simulated intestinal fluid and fasted state simulated intestinal fluid , which are presented in table 2 , table 3 and table 4 and fig1 , fig2 and fig3 . the spray drying process includes preparation of the spray solution to dissolve compound a and cellulose acetate phthalate ( cap ), spray drying to form spray - dried dispersion ( sdd ) powder , and secondary drying of the sdd powder to remove residual solvent . fig4 provides an overview of the process used to manufacture the 25 % sdd formulation containing 250 mg / g of compound a and 750 mg / g of cap ( referred to as 25 % compound a : cap sdd ) on a psd - 1 spray dryer . during spray solution preparation the temperature of the solution is maintained at room temperature but above 20 ° c . to ensure the solubility of compound a . after compound a is added to the acetone , the solution is mixed for at least one hour , until the crystalline compound a is completely dissolved . the cap is then added to the solution and mixed for at least one hour until the cap is completely dissolved . the spray solution contains 1 . 25 % of compound a , 3 . 75 % of cap and 95 % of acetone . the spray - drying conditions are divided into preheating , warm - up / shutdown and feed - solution processing phases . during the warm - up phase pure acetone is sprayed to thermally equilibrate the spray dryer . during the feed - solution processing phase the compound a : cap spray solution is sprayed . the operating conditions for the three phases are summarized in table 5 . the sdd powder is spread evenly on open trays and placed in a tray dryer and dried overnight to remove residual acetone ( in - process control : residual acetone & lt ; 0 . 2 %). drying parameters are listed below : tray dryer type : convection tray dryer temperature : 40 ° c .± 5 ° c . tray dryer relative humidity ( rh ): 15 % to 30 % rh ± 15 % drying time : 24 hr bed depth : ≦ 2 . 5 cm fig5 illustrates the residue acetone content as a function of tray - drying time at 40 ° c ./ 30 % rh for 25 % compound a : cap sdd based on headspace gas chromatography ( gc ) analysis under conditions having a tray - dryer bed depth of equal to or less than 2 . 5 cm . in one example , a spray solution was formed containing 1 . 25 wt % compound a , 3 . 75 wt % cap , and 95 % acetone as follows . compound a was added to acetone in a stainless - steel solution tank with a top - mounted mixer , and mixed for at least 1 hour . next , cap was added directly to this mixture , and the mixture stirred for at least one additional hour . the resulting mixture had a slight haze after the entire amount of polymer had been added . this mixture was then filtered by passing it through a filter with a screen size of 230 μm to remove any large insoluble material from the mixture , thus forming the spray solution . the spray - dried dispersion was then formed using the following procedure . the spray solution was pumped to a spray drier ( niro type xp portable spray - dryer with a liquid - feed process vessel [ psd - 1 ]) equipped with a pressure swirl atomizer ( spraying systems pressure nozzle and body ( sk 76 - 16 )). the psd - 1 was equipped with a 9 - inch chamber extension to increase the vertical length of the dryer . the spray drier was also equipped with a diffuser plate having a 1 % open area to direct the flow of the drying gas and minimize product recirculation within the spray dryer . the nozzle sat flush with the diffuser plate during operation . the spray solution was pumped to the spray drier at about 215 gm / min at a pressure of about 315 psig . drying gas ( e . g ., nitrogen ) was circulated through the diffuser plate at an inlet temperature of about 125 ° c . the evaporated solvent and wet drying gas exited the spray drier at a temperature of 45 ± 5 ° c . the sdd formed by this process was collected in a cyclone . solid non - crystalline dispersions of 10 or 25 % compound a with hpmcas - mg was also prepared . long - term storage of the sdd may be at an average of 5 ° c . ( e . g ., 2 ° c . to 8 ° c .) in double low - density polyethylene ( ldpe ) bags inside hdpe drums with desiccant between the two bags . the sdd may be stored for short - term , e . g ., 1 week , at ambient temperature and humidity ( e . g ., 25 ° c ./ 60 % rh ). in vitro analysis of spray - dried dispersion formulation with 25 % of compound a table 6 lists the general physical properties of a 25 % compound a : cap sdd manufactured from an acetone solution . * 10 vol % of the particles have a diameter that is smaller than d 10 ; 50 vol % of the particles have a diameter that is smaller than d 50 , and 90 vol % of the particles have a diameter that is smaller than d 90 . the potency and purity of the sdd were assessed by high - performance liquid chromatography ( hplc ), which indicated that sdd prepared from an acetone solution did not significantly change the purity of compound a and the potency was similar to the theoretical potency of the formulation . in vitro performance was evaluated using an in vitro dissolution test performed at a theoretical c max of 200 μg / ml of compound a in natc / popc in pbs ( ph 6 . 5 ), wherein c max is maximum observed concentration ; natc / popc is 3 . 7 / 1 sodium taurocholate / l - palmitoyl - 2 - oleoyl - sn - glycero - 3 - phosphocholine and pbs is phosphate buffer solution . samples were weighed , dissolved in the buffer system , centrifuged , and the supernatant analyzed by hplc at 10 , 20 , 40 , and 90 minutes . tables 7a and 7b and fig6 compares in vitro dissolution performance of compound a : cap sdd with that of crystalline of compound a , hpmcas - mg , and hpmcas - hg . as the figure shows , the c max and auc 0 - 90 ( area under the curve through 90 minutes ) of the sdd were more than 6 - fold higher than those of crystalline of compound a . the concentrations of compound a obtained in these samples were used to determine the maximum concentration of compound a (“ c max90 ”) and the area under the concentration - versus - time curve (“ auc 90 ”) during the initial ninety minutes . in vivo testing was performed in male dogs to compare the systemic exposure of the 25 % compound a : cap sdd ( n = 2 ) to that of the crystalline compound a ( n = 2 ). as shown in table 8 , the 25 % compound a : cap sdd provided a enhanced systemic exposure over bulk crystalline drug in male beagle dogs dosed at 10 mg / kg and 200 mg / kg compound a orally . tablet manufacture includes blending the sdd and intragranular excipients to form a uniform blend , dry - granulating to form flowable granules , blending extragranular excipients to provide additional tableting functionality , tablet compressing to form unit dosages , and film - coating to provide a white opaque coating . the excipients used in the 25 and 100 mg tablets are shown in tables 9 and 10 , respectively . a sufficient amount of the solid dispersion of compound a was used to provide for 25 mg of the compound in the 25 mg tablet , and a sufficient amount of the solid dispersion of compound a was used to provide for 100 mg of the compound in the 100 mg tablet . fig7 provides an overview of the manufacturing process for the uncoated 25 mg tablets . fig8 provides an overview of the manufacturing process for the uncoated 100 mg tablets . the same blending and dry - granulation process is used for the 25 mg and 100 mg active tablets ( i . e ., a “ common granulation ” is used for both tablet strengths ). the 25 and 100 mg uncoated tablets may have identical size , shape and weight . optionally , the 25 mg and 100 mg tablets can be coated using a film coating compositions well known to those of skill in the art , for example , opadry ii ( white 85f18378 , colorcon ) and purified water . 1 . the intragranular excipients are delumped by passing through a low - shear cone mill . 2 . the delumped excipients , and the 25 % compound a : cap sdd are added to the bin blender and blended . 3 . the magnesium stearate is hand screened with a portion of the blend from step 2 into the bin blender and blended . 4 . the blend is discharged from the blender and roller - compacted . the roller compactor parameters are established to provide roller compacted material with a solid fraction ( a unitless relative density parameter ) of 0 . 63 . this is assured by in - process measurement . 5 . the roller compacted material is granulated by passing through a 0 . 8 mm oscillating screen mill . the granulation from step 5 is called the “ common granulation ” and is used to manufacture both the 25 and 100 mg active tablets . the extragranular final blend and tablet compression are carried out as follows : 1 . the required amounts of extragranular excipients are calculated . 2 . for the 25 mg active tablets only , the granulation , extragranular lactose and extragranular microcrystalline cellulose are added to the bin blender and blended . 3 . the colloidal silica dioxide is hand screened with a portion of the blend from step 2 into the bin blender and blended . 4 . the magnesium stearate is hand screened with a portion of the blend from step 3 into the bin blender and blended . 5 . the powder is discharged from the blender and compressed into 800 mg total weight tablets using a rotary tablet press . the tablet weight , tablet weight distribution and tablet hardness are adjusted during startup and are monitored at timed intervals during compressing to assure product attributes are met . 6 . the tablets are de - dusted , passed through a metal detector and stored in double polyethylene bags in drums . in one particular example , crospovidone , lactose monohydrate , and microcrystalline cellulose were delumped using a comil 197 equipped with a 0 . 032 - inch ( 032r ) screen and 1601 impellor . the spray - dried dispersion was added to the delumped mixture and blended using a pk twin - shell blender , followed by addition and blending of the magnesium stearate , to form the intragranular blend . next , the intragranular blend was roller compacted and milled into granules using a gerteis mini - pactor with a gerteis star rotor mill with a 0 . 8 mm screen , a compression force between 4 and 7 kn / cm , and a roll speed between 2 and 6 rpm . the milled granulation was blended with colloidal silica dioxide , followed by the addition and blending of the extragranular magnesium stearate . tablets were compressed using a kilian t - 100 rotary press with 0 . 3586 ″× 0 . 7174 ″ modified oval tooling to a hardness of 17 - 23 kp . the aqueous film - coating process is the same for the 25 and 100 mg active tablets , which is described below and illustrated in fig9 . 1 . the opadry ii powder is added to purified water and stirred until no lumps remain . 2 . the coating pan is pre - warmed and then the empty pan is spray - coated with a thin layer of opadry ii to eliminate sliding of tablets during film - coating . 3 . tablets are added to the pan and pre - warmed . 4 . the tablets are film - coated and the coating suspension is stirred throughout the coating process to prevent settling . 5 . when the coating process is complete , the tablets are dried with jog tumbling . 6 . finished , coated tablets are stored in double polyethylene bags in drums . in one particular example , a coating solution was formed by adding opadry ii to purified water ( 1 : 9 wt : wt ) in a mixing vessel with overhead propeller stirrer . the coating solution was pumped using a peristaltic pump to a schlick 970 spray gun with 1 . 0 - mm nozzle and standard air cap , and the tablets were coated in a vector ldcs pan - coater . the following conditions were used : atomizing air pressure 15 psi , nozzle tip - to - bed distance 2 . 5 ″, inlet air flow 45 cfm , inlet - air temperature 70 to 75 ° c ., exhaust temperature 46 ° c ., pan run speed 20 rpm , and solution flow rate 9 g / min . coated tablets had a hardness of 20 kp . a sink dissolution test was performed on 100 - mga film - coated sdd tablets . 900 ml dissolution media ( 0 . 05 m nah 2 po 4 , ph 6 . 8 , containing 1 wt % sodium lauryl sulfate ) was added to 1000 ml vankel dissolution vessels and allowed to warm up for about 30 minutes . tests were performed at 37 ° c . four tablets were dropped into individual vessels containing the dissolution media at time 0 . the theoretical maximum concentration of compound a in the dissolution media was 11 μg / ml . samples ( 10 ml ) were taken at 5 , 15 , 30 and 45 minutes using 20 ml syringes with cannulas equipped with 10 μm full flow filters . the samples were filtered through a 0 . 45 μm nylon syringe filter into an hplc vial for analysis . the results are shown in table 11 . the 100 mg tablets released 98 . 3 % of theoretical by 45 minutes . tablets were greater than 80 % dissolved within 5 minutes . the tablets can be packed in high - density polyethylene ( hdpe ) bottles with polypropylene heat - induction seal caps and desiccant . bottles can be labeled with the lot number , content , storage conditions and other information as required . this is a single center , phase 1 , double - blind , placebo - controlled , multiple ascending dose study of compound a given orally as a reformulated tablet ( spray dried dispersion , or sdd ) to otherwise healthy subjects with “ pre - diabetes ” ( impaired fasting glucose , impaired glucose tolerance , or hba1c ≧ 5 . 8 ), or diet - controlled type 2 diabetes mellitus . the study was designed to evaluate the safety , tolerability , pharmacokinetics ( pk ), and proof - of - concept pharmacodynamics of compound a . each dosing cohort consisted of a screening period to assess eligibility , a dosing and observational period , and a follow - up period . the screening visit was used to assess preliminary eligibility in potential subjects who provided informed consent . final eligibility for study enrollment was determined after check - in to the clinic on day − 3 , before randomization and dosing ( on day 1 ). eleven eligible subjects who successfully completed screening were enrolled into the lowest dose cohort that was yet to be filled , and randomly assigned in a double - blind fashion to receive compound a ( n = 8 ) or matched placebo ( n = 3 ). up to 4 additional subjects were admitted to the clinic and available as back - ups in the event that 1 of the original 11 subjects was not dosed for any reason . each of these study cohorts was enrolled and completed independently , and in sequential fashion . after completion of the inpatient observational period at day 8 , blinded clinical safety and laboratory parameters ( including pk ) were assessed in a teleconference between the principal investigator , or sub - investigator , and the metabolex medical monitor , after which subject dosing assignments could have been unblinded , if necessary , for determination of dose - limiting toxicities ( dlts ). if two dose - limiting toxicities ( dlts ) occurred within the same treatment cohort in subjects receiving active drug , no further dose escalation would have been allowed , and the maximum tolerated dose ( mtd ) would have been defined by the dose in the previous cohort . additionally , dosing may have been halted at the discretion of the sponsor depending on observed compound a concentrations and pk parameters from the preceding cohort in context of the safety and pharmacodynamic profile of the preceding cohorts . the initial screening visit occurred between day − 35 and day − 4 , before the start of each new dose cohort , to determine subject eligibility . at the initial screening visit , subjects signed an informed consent prior to any study specific assessments or assignment of a screening number . screening evaluations included collection of demographics and a full medical history with medication review , 12 - lead ecg and vital signs ( including height and weight ), drug and alcohol screen , serum pregnancy test ( females only ), clinical laboratory evaluation and hba1c . a minimum of 15 subjects who satisfied initial screening eligibility assessments were invited to complete the day − 3 assessments . subjects returned to the clinic three days prior to scheduled drug administration ( day − 3 ) for a repeat safety and final eligibility evaluation consisting of vital signs ( including weight ), ecg , complete physical examination including funduscopic examination , clinical laboratory evaluation , repeat drug and alcohol screen , repeat serum pregnancy test ( females only ) and review of concomitant medications and interval medical history . each subject underwent a final eligibility review and up to 15 fully eligible subjects were admitted to the clinic overnight . on day − 2 , following a 10 hour overnight fast , up to 15 eligible subjects underwent a baseline mmtt administered between 9 : 30 and 10 : 15 am , for the assessment of glucose and insulin response and of total glp - 1 and glucagon . on day − 1 , following a 10 hour overnight fast , up to 15 eligible subjects also underwent a baseline ogtt ( 75 g ) administered at the identical time of day as the mmtt , for assessment of the same markers . after the baseline ogtt assessments , 11 subjects were enrolled and randomized into the current dosing cohort . up to 4 additional subjects remained overnight to be available as back - ups in the event that 1 of the original 11 subjects was , for any reason , not dosed . if more than 11 eligible subjects meet the cohort requirements , the excess subjects may have been included in the next cohort check - in , if within the 35 day screening window and they continued to meet eligibility . on days 1 through 5 , following a 10 hour overnight fast , subjects received daily doses of compound a or placebo exactly 2 hours earlier than the start of the baseline mmtt , under fasted conditions . the inpatient period in clinic began on day − 2 and concluded on day 8 , following the final inpatient study procedure . the following assessments were made in temporal relationship to the administration of the study drug , administered at day 1 , time 0 , unless otherwise stated : subjects randomized to compound a or placebo underwent single dose ( day 1 ) and repeat dose ( day 4 ) pk . compound a was measured pre - dose ( t − 30 and 0 min ) on day 1 and at 20 and 40 minutes , and 1 , 2 , 3 , 4 , 6 , 8 , 12 , and 24 hours post - dose . compound a was measured at identical timepoints associated with the day 4 dose , but included additional measurements at 48 and 72 hours post - dose ( day 7 ). additionally , a 24 hour urine collection was completed on day 4 for potential measurement of compound a and its metabolites . ae &# 39 ; s : reviewed and recorded just before study drug administration and twice daily during the inpatient observational period ( through day 8 ) complete physical examination including funduscopic examination : day 6 vital signs : days − 2 , − 1 , days 1 through 5 ( immediately pre - dose and at 15 , 30 , and 60 minutes and 2 , 4 , and 12 hours post - dose ), and days 6 , 7 , and 8 ecg : days 1 through 5 ( immediately pre - dose and at 2 , 4 , and 12 hours post - dose ), and days 6 , 7 , and 8 clinical laboratory : on days 1 ( pre - dose ), 2 , 4 , 6 , and 8 . concomitant medication review and recording of all medications used since screening , at every visit beginning at day − 2 and through the observational period . an mmtt was administered at baseline ( day − 2 pre - dose ) and at 2 hours after the day 4 dose , at the identical time on each occasion . glucose , and insulin were obtained from 7 measurements performed at 30 minutes before the meal , immediately before the meal ( 0 minutes ), and 30 , 60 , 90 , 120 , and 240 minutes after starting the meal . total glp - 1 and glucagon were obtained from 11 measurements performed at 30 minutes before the meal , immediately before the meal ( 0 minutes ), 10 , 15 , 20 , 30 , 40 , 60 , and 90 minutes after starting the meal , and at 2 and 4 hours after starting the meal . a 75 g ogtt was administered at baseline ( day − 1 pre - dose ) and at 2 hours after the day 5 dose , at the identical time on each occasion . glucose and insulin were obtained from 7 measurements performed at 30 minutes before the glucose ingestion , immediately before the glucose ingestion ( 0 minutes ), and 30 , 60 , 90 , 120 , and 240 minutes after the glucose ingestion . total glp - 1 and glucagon were obtained from 11 measurements performed at 30 minutes before the meal , immediately before the meal ( 0 minutes ), 10 , 15 , 20 , 30 , 40 , 60 , and 90 minutes after starting the meal , and at 2 and 4 hours after starting the meal . fasting glucose : day 1 pre - dose ( 2 samples , 5 minutes apart ) and day 5 pre - dose ( 2 samples , 5 minutes apart ) remaining sample material was banked for possible , future exploratory analyses related to this compound . this visit included vital signs , full physical examination including funduscopic examination , clinical laboratory evaluation , serum pregnancy test ( females only ), ecg , concomitant medication review , and review of ongoing ae &# 39 ; s . the completion of this visit marked the end of the subject &# 39 ; s formal participation in the study . 11 subjects ( 8 active , 3 placebo ) were to be randomized into the dosing phase of each of the four dosing cohorts of this study , for a total of 44 subjects . healthy , ambulatory , adult male and female volunteers between 18 to 60 years of age with no significant medical history as judged by the investigator history of type 2 diabetes mellitus allowed if diet - controlled and not treated with insulin or oral glucose lowering agents within 3 months of screening fasting glucose ≧ 100 mg / dl and ≦ 150 mg / dl or 2 hour post ogtt ( 75 g ) glucose & gt ; 140 mg / dl or hba1c ≧ 5 . 8 % at screening all clinical laboratory test results must have been within normal range or considered not clinically significant ecg must have been normal or without clinically relevant pathology as judged by the investigator ; all vital signs including blood pressure must have been within normal limits compound a ( 25 mg and 100 mg tablets ) or matched placebo . table 12 shows the baseline demographics of the phase 1c study . cohort 1 : 25 mg ( 25 mg × 1 ) orally once daily for 5 days cohort 2 : 100 mg ( 100 mg × 1 ) orally once daily for 5 days cohort 3 : 300 mg ( 100 mg × 3 ) orally once daily for 5 days cohort 4 : 600 mg ( 100 mg × 6 ) orally once daily for 5 days screening period : up to 33 days ( day − 35 to day − 3 ) dosing and observational period : 10 days ( day − 2 to day 8 ) follow - up phase : 7 days ( day 9 to day 15 ) in this study , single escalating doses ( 4 cohorts ) of the sdd formulation of compound a , administered in the fasted state , were well absorbed and led to a relatively linear dose - dependent increase in c max and exposure at all doses administered . relative to single doses of the microcrystalline formulation , exposure was enhanced by up to 4 . 2 - fold at the top dose ( 600 mg ). relative to single doses , repeat daily dose pk ( day 5 ) showed modest accumulation (˜ 2 - fold ) but by day 5 steady - state drug levels were nearly achieved . the repeat dose 24 h exposure at the highest dose ( 600 mg ) was ˜ 8 - fold higher than the maximum exposure previously achieved with the microcrystalline formulation . the repeat dose half - life was consistent with once daily dosing . a summary of the repeat dose ( day 5 ) concentration - time profile and pk parameters , by dosing group , is presented in fig1 and table 13 , respectively . a comparison of the auc and c max for the sdd formulation and the microcrystalline formulation are shown in fig1 and 12 , respectively . in the studies that have been conducted to date , compound a consistently lowered fasting plasma glucose ( fpg ) and glucose excursion following a mixed meal tolerance test ( mmtt ) and oral glucose tolerance test ( ogtt ). single doses of the microcrystalline formulation of compound a ( 600 mg and 1000 mg ) in study a , and repeat daily doses of 100 mg and 300 mg over 4 days in study b reduced the glucose excursion in a dose - dependent fashion during a mixed meal tolerance test compared to placebo and / or baseline by 20 - 40 %. repeat daily doses of the sdd formulation of compound a at all doses tested in study c ( 25 , 100 , 300 , and 600 mg ) reduced the glucose excursion during a mixed meal and oral glucose tolerance test compared to baseline and placebo . the magnitude of the glucose reduction observed during the mmtt was more pronounced , and ranged between 34 and 51 %, as shown in fig1 . with the sdd formulation , the peak glucose effects appeared to be observed at the 100 and 300 mg doses , while dosing of 600 mg ( up to exposures of & gt ; 50 , 000 ng * h / ml ) did not result in additional glucose lowering in this population of early pre - diabetics . at baseline , subjects in the 600 mg group had better glycemic tolerance than the other groups , which likely explains the apparent lower magnitude of effect at this dose . reductions in glucose were greatest in the subsets of subjects with the greatest degree of glucose intolerance at baseline ( up to 77 % reduction , net of placebo ). this is exemplified by a pooled subanalysis of subjects receiving any dose of compound a in phase 1c ( study c ), as depicted in fig1 .
this invention relates to the field of pharmaceutical chemistry and , more specifically , to pharmaceutical formulations as well as to intermediates used to prepare such formulations and to methods for manufacturing such formulations .