United States Patent [19]
`Rosenberg et al. (cid:9)
`
`4,857,552
`[11] Patent Number: (cid:9)
`[45] Date of Patent: Aug. 15, 1989
`
`[54] STABLE PHARMACEUTICAL
`COMPOSITION
`[75] Inventors: Leonard S. Rosenberg, Lake Villa;
`Cheryl Black, Vernon Hills; Earl R.
`Speicher, Buffalo Grove; Dietmar
`Wagenknecht, Waukegan, all of Ill.
`[73] Assignee: E. I. du Pont de Nemours and Co.,
`Wilmington, Del.
`[21] Appl. No.: 203,836
`Jun. 8, 1988
`[22] Filed: (cid:9)
` A61K 31/24; A61K 31/195
`[51] Int. C1 4 (cid:9)
` 514/538; 514/567
`[52] U.S. Cl. (cid:9)
` 514/538, 567
`[58] Field of Search (cid:9)
`References Cited
`[56]
`U.S. PATENT DOCUMENTS
`4,454,154 6/1984 Matier (cid:9)
`Primary Examiner—Frederick E. Waddell
`Attorney, Agent, or Firm—Gildo E. Fato
`
` 514/538
`
`ABSTRACT
`[57] (cid:9)
`An injectable, aqueous pharmaceutical composition for
`the treatment of cardiac conditions comprising an effec-
`tive amount of methyl 344-(2-hydroxy-3-iso-
`propylamino)propoxy]phenylpropionate hydrochloride
`(esmolol) for treating such a cardiac condition, said
`composition comprising about 1 mg to 250 mg of es-
`molol per milliliter of said injectable pharmaceutical
`composition; 0.01 to 0.02M buffer; said composition
`having a pH range of 4.5 to 5.5, the esmolol degrading
`in aqueous solution to produce 3-[4-(3-propionic acid)-
`phenoxy]-1-isopropylamino-2-propanol hydrochloride,
`3-[4-(3-propionic (cid:9)
`acid)-phenoxyl]-1-iso-
`said (cid:9)
`propylamino-2-propanol hydrochloride having a pK in
`the pH range of said composition to thereby act as a
`secondary buffer to increase the buffer capacity and
`minimize the change in pH as degradation occurs,
`whereby the stability of esmolol in an aqueous composi-
`tion is enhanced.
`
`8 Claims, No Drawings
`
`MYLAN ET AL. - EXHIBIT 1012
`
`(cid:9)
`(cid:9)
`

`
`1
`
`4,857,552
`
`STABLE PHARMACEUTICAL COMPOSITION
`
`2
`increase the buffer capacity and minimize the change in
`pH and thereby maximize the stability of esmolol in an
`aqueous composition.
`DETAILED DESCRIPTION OF THE
`INVENTION
`In accordance with the present invention, it has been
`discovered that a stable pharmaceutical composition
`possessing a relatively long shelf life can be prepared
`10 using a short-acting, ester-containing /3-blocker of the
`formula:
`
`15 (cid:9)
`
`BACKGROUND OF THE INVENTION
` 5
`The present invention relates to pharmaceutical com-
`positions. More particularly, the invention concerns
`novel compositions in which ester-containing 13-block-
`ing drugs are stabilized against hydrolysis during ship-
`ping and storage.
`In the past, the emphasis in /3-blocker research has
`been to develop stable drugs which could be adminis-
`tered to cardiac patients over relatively long periods of
`time. However, it is often desirable in the critical care
`setting to quickly reduce heart work or improve rhyth-
`micity during a cardiac crisis, e.g., during or shortly
`after a myocardial infarction. Conventional /3-blocking
`agents can be employed for such treatment, but their
`long durations of action can cause undesirable side ef-
`fects.
`Recently, certain compounds containing ester func- 20
`tions have been found to possess /3-adrenergic blocking
`activity. (See U.S. Pat. No. 4,387,103 to Erhardt, et al.,
`June 7, 1983, and U.S. Pat. No. 4,593,119, June 3, 1986.)
`These compounds generally have a short duration of
`action in vivo, and do not possess the disadvantages of 25
`the conventional 13-blockers described above. The ester
`groups in these compounds have, however, been found
`to be somewhat unstable in aqueous environments, such
`as intravenous infusion solutions. The practical effect of
`this instability is that conventional compositions con- 30
`taining the compounds have relatively short shelf lives,
`thus making commercial distribution and storage diffi-
`cult.
`Therefore, there remains a need for pharmaceutical
`preparations of short-acting 0-blockers which are stable 35
`in vitro and have a relatively long storage life.
`SUMMARY OF THE INVENTION
`In accordance with the present invention, disclosed
`herein is an aqueous pharmaceutical composition for the 40
`treatment or prophylaxis of cardiac disorders in a mam-
`mal comprising from about 1 mg to about 250 mg/mL
`of injectable pharmaceutical composition of a /3-adren-
`ergic blocking compound having the formula:
`
`OH He
`I (cid:9)
`I
`OCH2CHCH2N(CH3)2
`
`CH2CH2CO2CH3
`
`OH H+
`
`OCH2CHCH2N(CH3)2
`
`0
`
`CH2CH2CO2H
`
`45
`
`50
`
`55
`
`60
`
`or a pharmaceutically acceptable salt thereof, said com-
`pound (esmolol) degrading in aqueous solution to pro-
`duce (cid:9)
`3-[4-(3-propionic (cid:9)
`acid)-phenoxy]-1-iso- 65
`propylamino-2-propanol (degradation product), said
`degradation product having a pK in the pH range of the
`composition to thereby act as a secondary buffer to
`
`OH HO
`I (cid:9)
`I
`OCH2CHCH2N(CH3)2
`
`CH2CH2CO2CH3
`
`OH fl+
`
`OCH2CHCH2N(CH3)2
`
`CH2CH2CO2H
`
`or a pharmaceutically acceptable salt thereof, prefera-
`bly the hydrochloride salt.
`The stability of methyl 344-(2-hydroxy-2-iso-
`propylamino)propoxy]phenylpropionate (esmolol) in
`water is mediated by the rate of acid/base hydrolysis of
`the labile aliphatic methyl ester group. Current esmolol
`formulations use alcohol and propylene glycol to mini-
`mize the concentration of water in the formulation and,
`therefore, slow this degradation pathway. As an alter-
`native to the mixed organic/aqueous formulation, work
`has been done in totally aqueous solutions. This work
`has shown that the rate of degradation of esmolol can be
`reduced by:
`(1) use of acetate as the buffer,
`(2) maintaining the pH as near to pH= 5.0 as possible,
`(3) minimizing the concentration of esmolol in solu-
`tion, and
`(4) minimizing the concentration of buffer used.
`If these four conditions can be met, then it is possible
`to formulate esmolol in a totally aqueous solution with
`an acceptable shelf life.
`Each of the four conditions necessary for a stable
`aqueous esmolol solution, as outlined above, are dis-
`cused hereinafter. As is apparent, the shelf life of an
`aqueous esmolol formulation can be maximized by the
`correct choice of buffer, pH and esmolol concentration.
`The novel use of a 'secondary buffer' to minimize the
`buffer concentration is critical to the stability of the
`aqueous formulation.
`Buffers tested for their effect on the stability of es-
`molol were: acetate, tartrate, lactate, gluconate, sodium
`phosphate, and 3-[4-(3-propionic acid)-phenoxy]-1-iso-
`propylamino-2-propanol (degradation product). From
`these experiments, acetate buffer provided the best es-
`molol stability in aqueous solution. As such, it was
`chosen as the formulation buffer.
`The stability of esmolol in water has been determined
`from pH= 0 to pH= 12. The pH showing maximum
`
`

`
`4,857,552
`
`10
`
`55
`
`20
`
`3
`stablity was found to be pH =5.0±0.50. A pH stability
`profile in acetate buffer was run from pH= 4 to pH= 7.
`Maximum stability was found to be in a narrow pH
`range centered around pH= 5.0. The breadth of this
`stability appears to be very narrow (i.e. ±0.2 pH units). 5
`The rate of degradation of esmolol has been shown to
`decrease as the concentration of esmolol decreases. The
`preferred aqueous formulation described is 1% (10
`mg/mL) versus a 25% (250 mg/mL) glycol/alcohol
`based solution of esmolol. (cid:9)
`The choice of acetate as the buffer, the reduction in
`the concentration of esmolol in solution, and the main-
`tenance of the pH in a narrow range around pH =5 all
`favor a stability enhancement for esmolol in a totally
`aqueous media. The fourth condition necessary for an 15
`acceptably stables esmolol aqueous formulation is the
`reduction in the concentration of acetate buffer. In the
`absence of a 'secondary buffering' affect, a higher than
`desired concentration of acetate would be required to
`maintain the optimum pH. (cid:9)
`The concentration of acetate buffer necessary in solu-
`tion can be reduced to acceptable levels due to the
`nature of the degradation of esmolol in solution. This is
`because:
`(1) esmolol degrades to the degradation product in 25
`solution;
`(2) the degradation product has a pK of 4.80; and
`(3) this pK is in the pH range of the formulation.
`Thus, as esmolol degrades in aqueous solution it 'pro-
`duces' a secondary buffer which is active (i.e. has an 30
`additive effect on the buffer capacity of the formula-
`tion) in the pH range of the formulation. The equations,
`and their derivations, necessary to calculate the change
`in pH due to degradation in the presence of a secondary
`buffer are described hereinafter. By calculating the 35
`projected pH changes expected for the 1% formulation,
`it has been possible to minimize the amount of primary
`buffer (acetate) used in the formulation.
`Described is the identification, calculation and use of
`a degradation product as a secondary buffer to stabilize 40
`a formulation. The advantages of this secondary buffer-
`ing system are:
`(1) the secondary buffer is produced due to degrada-
`tion
`and, therefore, the buffer capacity increases as degra- 45
`dation occurs;
`(2) the concentration of primary buffer in the formu-
`lation
`can be minimized, thereby enhancing the stability of
`esmolol in a totally aqueous formulation. The majority 50
`of the buffering capacity of the formulation is due to the
`secondary buffer being produced, and not due to the
`primary acetate buffer. This is enhanced since,
`(3) the pK of the secondary buffer, the degradation
`product, (cid:9)
`is just below the initial pH (i.e. the pH of maximum
`stability).
`This maximizes the buffer capacity of the secondary
`buffer and reduces the change in pH due to degradation.
`The stability and shelf life of esmolol in an aqueous 60
`formulation is thereby increased. Another advantage of
`the totally aqueous formulation is that there are no
``extra' routes of degradation possible. The only possible
`competing reaction, in the totally aqueous formulation
`of esmolol, is the recombination of the degradation 65
`product and methanol to reform esmolol.
`The pH of a parenteral pharmaceutical product is
`normally set at an optimal value for stability, solubility
`
`4
`and other formulation factors. With time, most drugs
`will begin to degrade in solution. This degradation can
`cause a change in the pH of the solution, due to the
`production or consumption of acid or base. An accurate
`prediction of the change in pH is useful in formulating
`a drug, as well as predicting the shelf life expectancy of
`the formulation.
`An accurate prediction of the change in pH due to
`degradation is a straightforward problem when the
`degradation product(s) do not interfere with the calcu-
`lations. In these cases a simple Henderson-Hasselbalch
`equation can be used to predict the change in the pH of
`the solution. However, if the degradation creates a
`compound with an ionizable group (secondary buffer),
`then the prediction of the pH change, by calculation,
`may need to include and correct for this. In order to
`perform these calculations it is necessary to know the
`type of ionizable group (acidic or basic) created by the
`degradation, and the protonation state of this group
`immediately subsequent to its formation. The type of
`group (acid or base), protonation state, and the pH of
`the solution will then determine whether a hydronium
`or hydroxide ion is donated to, or consumed from, the
`solvent by the secondary buffer. The three possible
`cases are:
`(1) the pK of the secondary buffer is much greater
`than the pH of the solution;
`(2) the pK of the secondary buffer is much lower than
`the pH of the solution; and
`(3) the pK of the secondary buffer is comparable to
`the pH of the solution.
`Presented are equations to accurately calculate the pH
`change for the degradation of esmolol (i.e. the degrada-
`tion product acts as a secondary buffer, case 3).
`Esmolol degrades by a water mediated hydrolysis of
`its aliphatic carboxy methyl ester, to the degradation
`product noted and methanol. The resulting degradation
`product as a pK of 4.80 which is within the pH range
`(formulation pH ± 1.0) of the desired formulation. This
`secondary buffer (degradation product) affects the
`change in the pH due to its ability to act as a buffer.
`Equations to correct the calculated pH, due to this
`secondary buffering effect, are presented. The equa-
`tions presented accurately predict the pH change due to
`degradation when the secondary buffer is an acid. Deri-
`vation of equations to correct for the secondary buffer-
`ing of a basic compound can be made from the equa-
`tions presented.
`The pK for the aliphatic amino group of esmolol was
`determined by a differential potentiometric method.
`This method has been extensively described (L. S. Ro-
`senberg, et al., Drug Development and Industrial Phar-
`macy, 12(10), 1449-1467, (1986). The pK for the ali-
`phatic carboxy group of the degradation product of
`esmolol was determined by a routine potentiometric
`titration method, using the same method as described
`previously. Both pKs were determined in aqueous solu-
`tion.
`The degradation kinetics of esmolol were determined
`by monitoring the loss of esmolol by an HPLC routine.
`The HPLC procedure use a 15 cm, uBondapak Cyano
`column (Waters) and a Hitachi 655-11A pump with a
`Hitachi 655A variable wavelength UV detector set at
`214 nm. The mobile phase was acetonitrile:0.1 M so-
`dium acetate:glacial acetic acid; 15:84:1, at a 1 mL/min
`flow rate. Samples were diluted into 3 mL of milli-Q
`water to quench the degradation and then kept at room
`temperature until they were analyzed. The rate of deg-
`
`

`
`5
`radation at room temperature is minimal, and the sam-
`ples were assayed within a week of sampling.
`The change in pH due to degradation was determined
`using an ION 85 Radiometer with a semi-micro Ross
`electrode. All samples were allowed to cool to room 5
`temperature before the pH was measured.
`Routinely in the development of a parenteral product
`a number of buffer systems are investigated to assess
`their relative affects on the stability of the formulation.
`If the change in the pH due to degradation is known, 10
`apriori, then the concentration of buffer necessary for
`optimal pH maintenance can be predicted. This can
`reduce the number of formulation screens necessary to
`optimize a drug's formulation. (cid:9)
`The change in pH, due to degradation, of an aqueous
`formulation using an acetic acid/acetate buffer can be
`calculated by the Henderson-Hasselbalch equation:
`
`15
`
`[11+] = Ka* (cid:9)
`
`+ Cd
`[Ala — Cd
`
`where
`
`[HA10 —
`
`[H+], * Cr
`[H+]0 + Ka
`
`and
`
`Ka * Cr (cid:9)
`[A-lo
` — [H+], + Ka
`
`(1) 20
`
`(2) 25
`
`(3)
`
`30
`
`35
`
`where [HA]a and [A —]0 are the relative concentrations
`of acetic acid and acetate, respectively. [H +]0 is the
`hydrogen ion concentration at the initial pH, Ka is the
`ionization constant of the buffer, and Ct is the total
`initial concentration of the buffer. [H+] is the hydrogen
`ion concentration at any amount of degradation and Ca
`is the molar concentration of base consumed or acid
`produced, due to the hydrolysis of esmolol. Equation 1 40
`can be used to predict the change in the pH of a formu-
`lation for any percent drug loss.
`Assuming that the result of hydrolysis is to produce a
`product which has a pK in the pH range of the formula-
`tion, then equation 1 is modified to account for the 45
`increased buffer capacity of the secondary buffer by:
`
`[H+] = Ka* [HA] + Cd — [DH]
`[A — ] — Cd + [DH]
`
`(4) 50
`
`where [DH] is the concentration of secondary buffer
`produced due to degradation. Assuming that one mole
`of this secondary buffer is produced per mole of drug
`degraded, then the concentration of secondary buffer
`can be calculated by:
`
`[H]"Cd
`[DH] = [11+] + Kd
`
`(5)
`
`where [H+] is the hydrogen ion concentration at the
`calculated pH and Ka is the ionization constant of the
`secondary buffer. Combining equation 4 and 5 and rear-
`ranging gives: (cid:9)
`
`[11+]2[A — ]o+[H+]"(Kd[A —la—Cdf‘d—[1.1A]0Ka)
`—KaKd*([HA]a+Cd)=0 (cid:9)
`
`(6)
`
`55
`
`60
`
`65
`
`4,857,552
`
`6
`Equation 6 can be solved by the quadratic equation
`for any initial pH and concentration of buffer to give the
`pH for any percent degradation.
`In equation 4, the concentration of secondary buffer
`produced mediates the decrease in pH by its ability to
`consume acid produced by the hydrolysis of esmolol.
`Many times the active drug, or the excipients, do not
`degrade in such a fashion that the products have an
`ionizable group(s). In these cases, the only buffering
`capacity of the formulation will be that of the primary
`buffer. The concentration of primary buffer will have to
`be large enough to prevent significant pH changes. The
`amount of buffer necessary will vary according to the
`drug, pH-stability requirements, ionic strength effects,
`and other formulation factors. The change in the initial
`formulation pH, due to degradation, can be accurate
`predicted by equation 1.
`If the rseult of degradation is to create a product with
`an acidic ionizable group, which has a pK more than 2
`pH units higher than the pH of the formulation, then the
`pH of the solution will not change due to degradation.
`This assumes that the degradation reaction consumes
`one mole of base (produces one mole of acid) and pro-
`duces one mole of secondary buffer for each mole of
`drug lost. Then the secondary buffer will consume one
`mole of acid to protonate the 'created' conjugate base
`for each mole of degraded active drug substance. This is
`the 'best case' possible. The pH will not change due to
`hydrolysis of the esmolol and, therefore, the concentra-
`tion of primary buffer necessary can be minimized.
`Previous experiments have shown that esmolol de-
`grades by hydrolysis of its aliphatic methyl ester con-
`suming one mole of hydroxyl ions for each mole of
`esmolol degraded. The degradation product and one
`mole of methanol are the only degradation products.
`This degradation pathway results in the net production
`of one mole of acid for each mole of esmolol degraded.
`The secondary buffer is 'produced' in its conjugate base
`form. The degradation product increases the buffer
`capacity of the formulation as it is formed, thereby
`minimizing the change in pH due to degradation. Thus,
`the buffer capacity of the formulation increases as the
`amount of degradation increases. This allows the pri-
`mary buffer concentration to be reduced initially and
`set according to stability, isotonicity and other formula-
`tion factors.
`The stability of esmolol in aqueous solution is af-
`fected by several formulation factors. First, the optimal
`pH for stability, in acetate buffer, is found to be in a
`narrow range centered around pH= 5.0. Secondly, the
`concentration of acetate buffer affects the stability of
`esmolol in solution. Experiments have shown that the
`rate of hydrolysis of esmolol is dependent on the con-
`centration of acetate buffer. As the concentration of
`acetate is increased, the rate of hydrolysis of esmolol
`also increases.
`In the formulation of many parenteral compounds
`this sort of dictomy exists. The need to increase one
`component of the formulation for stability, in fact, com-
`promises the product's shelf life due to other competing
`solution factors. However, it has been found that if the
`problem is pH versus buffer capacity and the drug de-
`grades to produce a secondary buffer, then this formula-
`tion problem can be circumvented.
`The actual change in the pH due to degradation of
`esmolol is shown in Table I. For comparison purposes,
`the calculated change in pH with and without correc-
`tion for a secondary buffer is also listed. For the 50
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`4,857,552
`
`8
`TABLE I-continued
`Predicted versus Actual Change in the Formulation pH Due to
`Degradation
`initial is pH = 5.0
`Percent
`Un-
`De-
`corrected*
`graded
`pH
`
`Acetate
`Buffer
`
`Esmolol
`(mg/mL)
`
`Corrected+
`pH
`
`Actual
`pH
`
`7 (cid:9)
`mg/mL (5%) formulation, the change in the uncor-
`rected pH (no secondary buffering affect) is rapid for
`the 0.01 M buffer. By 20% esmolol degradation, this pH (cid:9)
`is less than 2. For the 0.05 M buffer, the buffer capacity (cid:9)
`is completely compromised by 20% degradation and its 5
`pH is less than 3. At 0.10 M buffer concentration, the
`pH does not decrease as dramatically, however, the pH
`is not maintained within 0.5 pH units of the initial pH.
`Therefore, in the absence of a secondary buffering af-
`fect, more than 0.10 M acetate buffer would be neces- 10
`sary initially.
`In the presence of a secondary buffering affect, the
`pH of the 50 mg/mL formulation is maintained within
`0.5 pH units of the initial pH of the 0.05 M acetate
`buffer. Even for 0.01 M acetate buffer, the formulations 15
`buffer capacity is not completely neutralized by 20% (cid:9)
`degradation. Therefore, the concentration of acetate (cid:9)
`
`buffer necessary for pH maintenance over the shelf life
`
`of this product can be reduced by more than a factor of (cid:9)
`two by the formation of a secondary buffer. (cid:9)
`For the 100 mg/mL (10%) formulation of esmolol, (cid:9)
`the change in pH due to degradation in the absence of a (cid:9)
`secondary buffering affect is dramatic. At even 0.10 M (cid:9)
`acetate buffer, the pH decreases to less than 2.5 for 20%
`degradation. Substantially more than 0.10 M acetate 25
`buffer would be required to maintain the pH within
`optimal limits. However, due to the presence of a sec-
`ondary buffering affect, the concentration of primary
`buffer can be set at 0.10 M.
`
`20 (cid:9)
`
`30
`
`0.10 M
`
`50
`
`100
`
`'Equation I
`+Equation 4
`
`20
`5
`10
`15
`20
`5
`10
`15
`20
`
`1.45
`4.85
`4.70
`4.55
`4.38
`4.70
`4.38
`3.93
`2.42
`
`4.33
`4.91
`4.83
`4.77
`4.72
`4.83
`4.72
`4.58
`4.52
`
`-
`4.90
`4.83
`4.73
`4.69
`4.85
`4.72
`4.58
`4.52
`
`TABLE II
`Predicted versus Actual Change in the Formulation pH Due to
`Degradation
`pH initial is pH = 5.5
`Acetate buffer concentration is 0.05 molar
`
`Concentration
`(mg/mL)
`
`Percent
`Degraded
`
`Uncorrected*
`pH
`
`Corrected+
`pH
`
`Actual
`pH
`
`10
`
`50
`
`5
`10
`15
`20
`5
`10
`15
`20
`
`5.39
`5.30
`5.21
`5.13
`5.06
`4.74
`4.42
`3.96
`
`5.41
`5.34
`5.27
`5.22
`5.17
`4.99
`4.86
`4.76
`
`5.40
`5.33
`5.25
`-
`5.15
`4.95
`-
`-
`
`FIG. 1
`
`OH Ha)
`I (cid:9)
`I (cid:9)
`OCH2CHCH2N(CH3)2 (cid:9)
`
`O
`
`CH2CH2CO2CH3
`
`OH }I+
`
`OCH2CHCH2N(CH3)2
`
`CH2CH2CO2H (cid:9)
`
`TABLE I
`Predicted versus Actual Change in the Formulation pH Due to (cid:9)
`Degradation
`pH initial is pH = 5.0
`Percent
`Un-
`De-
`corrected*
`graded
`pH
`
`Acetate
`Buffer
`
`Esmolol
`(mg/mL)
`
`Corrected+
`pH
`
`Actual
`pH
`
`0.01 M
`
`50
`
`100
`
`0.05 M
`
`50
`
`100
`
`5
`10
`15
`20
`5
`10
`15
`20
`5
`10
`15
`20
`5
`10
`15
`
`2.68
`1.98
`1.72
`1.56
`1.98
`1.56
`1.35
`1.21
`4.70
`4.38
`3.93
`2.72
`4.38
`2.72
`1.73
`
`4.48
`4.26
`4.11
`4.00
`4.26
`4.00
`3.84
`3.73
`4.83
`4.72
`4.62
`4.55
`4.72
`4.55
`4.43
`
`4.56
`4.21
`4.05
`-
`4.33
`4.02
`3.75
`3.63
`4.86
`4.67
`4.59
`-
`4.79
`4.47
`4.35
`
`'Equation I
`+Equation 4
`
`35
`
`EXAMPLE 1
`The following describes the preparation of vials of a
`pharmaceutical composition of the present invention
`40 containing 10 mL of solution with a concentration of
`esmolol HC1 of 10 mg/mL. The concentration of each
`ingredient of the composition, in an amount per mL
`solution, was as follows:
`
`45 (cid:9)
`
`(cid:9) 50 (cid:9)
`
`Esmolol HCI (cid:9)
`Sodium Acetate • 3H20 (cid:9)
`Glacial Acetic Acid USP (cid:9)
`Sodium Hydroxide Solution (ION) (cid:9)
`Hydrochloric Acid Solution (5N) (cid:9)
`Water for Injection USP (cid:9)
`
`
`Amount/mL Solution
`
`10 mg
`2.8 mg
`0.546 mg
`pH adjusted to 5.0
`pH adjusted to 5.0
`qs
`
`The vials and glassware for compounding, filtering
`55 and filling were washed and depyrogenated. The filter
`assembly, filling tube assembly, and other parts and
`equipment were sterilized.
`Seventy-six percent of the final volume of cool water
`for injection was collected in a compounding tank. The
`60 sodium acetate was added and the solution was stirred
`until the sodium acetate dissolved. The glacial acetic
`acid was then added and the solution was stirred for 5
`minutes after which the esmolol HC1 was added and
`stirring was continued until all of the ingredients were
`65 dissolved. The pH of the solution is then adjusted to 4.9
`to 5.1 using hydrochloric acid or sodium hydroxide.
`The solution is then brought to final volume with cool
`water for injection, 25° C.±5° C. and the pH is adjusted
`
`

`
`9
`to 4.9 to 5.1 if necessary. The solution was then placed
`in vials which were sealed, leak tested and inspected.
`
`EXAMPLE 2
`Vials prepared according to the procedure of Exam-
`ple 1 were selected and placed on stability test. At each
`stability time one ampul of each solution was removed.
`The pH, potency and the physical appearance of the
`solutions were determined. The concentration of the
`drug was determined by a high performance liquid
`chromatographic (HPLC) method. Each vial contained
`10 mL of solution and was stored in the inverted posi-
`tion which is an aggressive test because of the solution
`to stopper contact. The results are tabulated in Table
`III.
`The glossary for the abbreviations used in the table is
`as follows:
`TZ-Initial, zero time
`RT-Room temperature, 15° to 30° C.
`EL40-40° C.
`EL55-55° C.
`EL75-75° C.
`MOS-Months
`Samples were dissolved or diluted with the mobile
`phase, methanol-pH 3.4 phosphate buffer solution.
`The resulting solutions were diluted with benzoic acid
`internal standard solution and chromatographed on a
`octadecyl silane column with detection at 229 nm. The
`selectivity of the chromatographic system for intact
`compound was demonstrated by resolving the parent
`drug from synthetic intermediates, potential impurities
`and reaction products resulting from accelerated degra-
`dation conditions. The method is linear, quantitative,
`rugged and reproducible with a sensitivity of 2 µg/mL.
`Either peak height or peak area ratios can be used for
`quantitation.
`
`4,857,552
`
`10
`esmolol/mL of solution; 0.01 to 0.04 M buffer; said
`composition having a pH range of about 4.5 to 5.5, the
`esmolol degrading in aqueous solution to produce 3-[4-
`acid)-phenoxy]-1-isopropylamino-2-
`(3-propionic (cid:9)
`5 propanol hydrochloride, said 3-[4-(3-propionic acid)-
`phenoxy]-1-isopropylamino-2-propanol hydrochloride
`having a pK in the pH range of said composition to
`thereby act as a secondary buffer to increase the buffer
`capacity without the addition of buffer and minimize
`10 the change in pH as degradation occurs, whereby the
`stability of esmolol in an aqueous composition is en-
`hanced.
`2. The composition of claim 1 wherein the buffer is
`selected from the group comprising acetate, tartrate,
`15 lactate, gluconate and phosphate buffer.
`3. The composition of claim 2 wherein the buffer is
`acetate buffer.
`4. The composition of claim 3 including about 10
`mg/mL of solution.
`5. The composition of claim 4 wherein the concentra-
`tion of acetate buffer is about 0.05 M.
`6. The composition of claim 5 wherein a pH of about
`4.9 to about 5.1.
`7. A stable, injectable, aqueous pharmaceutical corn-
`25 position for the treatment of cardiac conditions com-
`prising an effective amount of Methyl 3-[4-(2-hydroxy-
`3-isopropylamino)propoxy]phenylpropionate hydro-
`chloride (esmolol) for treating such a cardiac condition,
`said composition comprising about 10 mg of es-
`30 molol/mL of solution; about 0.05 M buffer; said compo-
`sition having a pH range of about 4.5 to 5.5, the esmolol
`degrading in aqueous solution to produce 3-[4-(3-pro-
`pionic acid)-phenoxy]-1-isopropylamino-2-propanol
`hydrochloride, said 3-[4-(3-propionic acid)-phenoxy]-1-
`35 isopropylamino-2-propanol hydrochloride having a pK
`in the pH range of said composition to thereby act as a
`
`20 (cid:9)
`
`TABLE III
`Stability of the Formulation at Various Temperatures and
`Times
`
`Potency
`(Active)
`Value Change
`(%)
`
`pH
`Change
`Value (cid:9)
`(pH)
`
`Physical Observations
`
`110.0
`
`105.8
`106.0
`101.7
`101.0
`
`102.5
`100.9
`90.3
`
`74.3
`56.0
`
`107.8
`109.5
`106.6
`107.3
`109.1
`
`0.0
`
`-4.2
`-4.0
`-8.3
`-9.0
`
`-7.5
`-9.1
`-19.7
`
`-35.7
`-54.0
`
`-2.2
`-0.5
`-3.4
`-2.7
`-0.9
`
`5.04
`
`5.01
`5.00
`4.96
`4.93
`
`4.91
`4.90
`4.81
`
`4.65
`4.51
`
`5.03
`5.03
`5.03
`5.04
`5.02
`
`0.0
`
`CLEAR COLORLESS SOLUTION
`
`-0.0
`-0.0
`-0.1
`-0.1
`
`-0.1
`-0.1
`-0.2
`
`-0.4
`-0.5
`
`-0.0
`-0.0
`-0.0
`0.0
`-0.0
`
`CLEAR COLORLESS SOLUTION
`CLEAR COLORLESS SOLUTION
`CLEAR COLORLESS SOLUTION
`CLEAR COLORLESS SOLUTION
`
`CLEAR COLORLESS SOLUTION
`CLEAR COLORLESS SOLUTION
`CLEAR COLORLESS SOLUTION
`
`CLEAR COLORLESS SOLUTION
`CLEAR COLORLESS SOLUTION
`
`CLEAR COLORLESS SOLUTION
`CLEAR COLORLESS SOLUTION
`CLEAR COLORLESS SOLUTION
`CLEAR COLORLESS SOLUTION
`CLEAR COLORLESS SOLUTION
`
`Test
`Time
`ALL
`TZ
`EL40
`1 mos
`2 mos
`3 mos
`6 mos
`EL55
`I mos
`2 mos
`3 mos
`EL75
`1 mos
`2 mos
`RT
`1 mos
`2 mos
`3 mos
`6 mos
`9 mos
`
`What is claimed is:
`1. An injectable, aqueous pharmaceutical composi-
`tion for the treatment of cardiac conditions comprising
`an effective amount of Methyl 344-(2-hydroxy-3-iso- 65
`propylamino)propoxy]phenylpropionate hydrochloride
`(esmolol) for treating such a cardiac condition, said
`composition comprising about 1 mg to about 250 mg of
`
`secondary buffer to increase the buffer capacity without
`the addition of buffer and minimize the change in pH as
`degradation occurs, whereby the stability of esmolol in
`an aqueous composition is enhanced.
`8. The composition of claim 7 having a pH of about
`4.9 to about 5.1.
`
`* * * * *